\r\n\tHomeostasis is brought about by a natural resistance to change when already in the optimal conditions, and equilibrium is maintained by many regulatory mechanisms. All homeostatic control mechanisms have at least three interdependent components for the variable to be regulated: a receptor, a control center, and an effector. The receptor is the sensing component that monitors and responds to changes in the environment, either external or internal. Receptors include thermoreceptors and mechanoreceptors. Control centers include the respiratory center and the renin-angiotensin system. An effector is a target acted on to bring about the change back to the normal state. At the cellular level, receptors include nuclear receptors that bring about changes in gene expression through up-regulation or down-regulation and act in negative feedback mechanisms. An example of this is in the control of bile acids in the liver. \r\n\tSome centers, such as the renin-angiotensin system, control more than one variable. When the receptor senses a stimulus, it reacts by sending action potentials to a control center. The control center sets the maintenance range—the acceptable upper and lower limits—for the particular variable, such as temperature. The control center responds to the signal by determining an appropriate response and sending signals to an effector, which can be one or more muscles, an organ, or a gland. When the signal is received and acted on, negative feedback is provided to the receptor that stops the need for further signaling.
\r\n
\r\n\tThe cannabinoid receptor type 1 (CB1), located at the presynaptic neuron, is a receptor that can stop stressful neurotransmitter release to the postsynaptic neuron; it is activated by endocannabinoids (ECs) such as anandamide (N-arachidonoylethanolamide; AEA) and 2-arachidonoylglycerol (2-AG) via a retrograde signaling process in which these compounds are synthesized by and released from postsynaptic neurons, and travel back to the presynaptic terminal to bind to the CB1 receptor for modulation of neurotransmitter release to obtain homeostasis. \r\n\tThe polyunsaturated fatty acids (PUFAs) are lipid derivatives of omega-3 (docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA) or of omega-6 (arachidonic acid, ARA) and are synthesized from membrane phospholipids and used as a precursor for endocannabinoids (ECs) mediate significant effects in the fine-tuning adjustment of body homeostasis.
\r\n
\r\n\t \r\n\tThe aim of this book is to discuss further various aspects of homeostasis, information that we hope to be useful to scientists, clinicians, and the wider public alike.
",isbn:"978-1-80355-478-5",printIsbn:"978-1-80355-477-8",pdfIsbn:"978-1-80355-479-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"63eb775115bf2d6d88530b234a1cc4c2",bookSignature:"Dr. Gaffar Sarwar Zaman",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11676.jpg",keywords:"Optimal Functioning, Body Temperature, Fluid Balance, Core Temperature, Blood Glucose, Iron Levels, Malfunction, Inherited Defect, Respiratory Center, Arterial Blood, Insulin, Baroreceptors",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 13th 2022",dateEndSecondStepPublish:"July 15th 2022",dateEndThirdStepPublish:"September 13th 2022",dateEndFourthStepPublish:"December 2nd 2022",dateEndFifthStepPublish:"January 31st 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"18 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Zaman is a member of the Medical Council of India, the Association of Medical Biochemists of India, and the Association of Clinical Biochemists of India. 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\n\t\t\t
1. Introduction
\n\t\t\t
To combat ischemic heart disease in the clinical scenarios of open heart surgery, unstable coronary syndromes, percutaneous coronary interventions, or thrombolysis, different research approaches are used to improve clinical treatments. The most dreaded long term consequence of ischemic heart disease – heart failure – is another clinical diagnosis where the treatment we have to offer is less than optimal. Some researchers are attempting to omit the reason for cardiovascular disease through targeting the process of atherosclerosis. Others adress the pathophysiology of restenosis, which may occurr after balloon dilatation of atherosclerotic lesions. Yet others adress improved treatment of the myocardium which has undergone an infarction, where the building of new blood vessels, strengthening of the contractile apparatus, and recruitment of new cells to areas of necrosis may be therapeutical end-points. Arrthythmias may occur due to reperfusion injury, after long-term morphological changes in the heart, or due to endogenous causes related to changes of the conduction system; new therapies are required for improved treatment. Novel treatments for dysfunctional, calsified heart valves are subject to other lines of investigations. Gene therapy and cell therapy using genetic engineering of stem cells will be the focus of this chapter, in particular the current status of treatments directed towards the myocardium itself in ischemic heart disease will be discussed. Gene therapy and to a lesser extend cell therapy have been used both clinically and experimentally to combat acute ischemia, remodeling and heart failure. However, the protected location of the heart of the heart inside the thoracic cavity, the nature of cardiac cells with minimal ability of entering cell cycle, and the electrophysiological properties of the heart render this organ with some particular challenges for gene therapy.
\n\t\t
\n\t\t
\n\t\t\t
2. Gene therapy for myocardial protection
\n\t\t\t
Delivery of DNA to hearts as well as other organs has been performed in animal experiments, and clinical studies in “no-option” patients have been conducted. Many clinical trials with gene therapy in cardiovascular patients have recently been reviewed (Lavu at al., 2010, Lyon et al., 2011). A general challenge with gene delivery to the heart is low transfection efficacy (the cardiomyocyte does not enter cell cycle), cell injury/inflammation, and unwanted sideeffects. There are several options on routes of DNA delivery to the heart. One alternative is intravascular delivery, which can be directed through coronary arteries or retrogradely into the coronary sinus. An arterial approach which requires open coronary arteries may not be suitable for patients with coronary artery disease if the target is treating cardiomyocytes rather than vascular cells. Pericardial gene delivery has been attempted, but there are rather few publications with that particular route of delivery. Another option is direct intracardiac delivery, which has been tried clinically and experimentally (Isner, 2002, Semenza, 2004, Vinge et al., 2008). In general it is difficult to achieve a lasting transfection through this invasive approach, which may be delivery of naked DNA or DNA ligated to a vector. Viral vectors used for cardiovascular therapy are most commonly adenovirus, adenoasscociated virus, and to a lesser extent lentivirus. A third possibility is systemic delivery with “something” that directs the DNA/RNA to a specific cell. The “something” in question may be adenovirus or adenoassociated virus, which have been most extensively used for genetic correction of cardiovascular disorders. Adenovirus have the advantage of being easy to manipulate, can be produced in high titers, and have a large transgene cloning capacity (Vinge et al., 2008). However, adenovirus elicit an inflammatory response. Development of so-called “gutted or gutless” adenovirus, where the immunogenic viral epitopes are removed, may become an option in the future (Vinge et al., 2008). Adenoassociated virus are not associated with any human disease, produce a stable and long-lasting gene expression, and easily transfect cardiac muscle cells. The latter is especially the case with some of the newer serotypes, of which serotype 9 is most cardiotropic (Bush et al., 2008, Zancarelli et al., 2008). A disadvantage is that only small constructs (less than 5 kb) can be packed into adenoassociated virus (AAV). Non-viral vectors are also in use and will be briefly discussed.
\n\t\t\t
Further considerations in cardiac gene therapy are which cells are to be treated and what do we want to overexpress or silence (Vinge et al., 2008). The possibilities range from targeting the vasculature to stabilize atherosclerotic plaques, prevent neointima formation, reduce atherosclerosis, induce angiogenesis, to improve survival of cardiomyocytes, improve function of cardiomyocytes, to reduce pathologic remodelling, and to prevent arrhythmia generation. Choice of gene construct and delivery route will depend on this. Genes encoding for factors which have intracellular effects should be delivered to a large population of cells to correct the underlying pathology, while genes encoding for secretory factors require fewer successfully transfected cells provided gene expression lasts (Isner, 2002). RNA interference or silencing, a possibility for gene knockdown, is predominantly at an animal experimental level. Experimentally, RNA interference though short hairpin RNA silencing the RNA polymerase of Coxsackie B3 virus packed into AAV2 successfully treated cardiac dysfunction in mice with coxsackieB cardiomyopathy (Fechner et al., 2008). In that study, the AAV2-construct was given intravenously. The same group have also used phospholamban silencing in short hairpin RNA delivered systemically through a AAV9 vector to normalize left ventricular remodelling after phenylephrine-induced hypertrophy (Suckau et al., 2009). RNA silencing will not be discussed further in this chapter.
\n\t\t\t
\n\t\t\t\t
2.1. Viral vectors
\n\t\t\t\t
The first experimental studies on cardiac gene therapy used intramyocardial delivery with plasmid DNA, demonstrating the feasibilty of envisioning cardiac gene transfer (Ascadi et al., 1991, Lin et al., 1990, Buttrick et al., 1992). Although those studies were successful in the terms of being able to cause transgene expression up to six months later in cardiomyocytes, the number of transfected myocytes was estimated to be as low as 60-100 cells (Ascadi et al., 1991). This lead to the search for vectors to enhance nuclear uptake, where viral vectors have been most extensively studied. Adenovirus was first attempted. Guzman and coworkers injected an adenoviral vector containing β-galactosidase (1993) into the myocardium, and was able to see a stronger signal than that evoked by plasmid containing the same molecular marker. However, the expression lasted only one week, and was accompanied by an inflammatory response (Guzman et al. 1993). Subsequently viral titers and protein production have been extensively studied and optimized, as have anatomic location and duration of adenoviral based gene expression in the heart (French et al., 1994, Magovern et al., 1996, Barr et al., 1994). Delivery of therapeutic genes with adenoviral vectors has been performed with success. For instance, adenoviral based delivery of DNA encoding for β2-adrenoceptors enhanced cardiac function in hamsters with cardiomyopathy (Tomiyasu et al., 2000). However, although adenovirus was the first vector to be used for cardiac gene therapy and has been useful for “proof of concept” as well as some initial clinical trials (Lavu et al., 2010), it may not be of large scale therapeutic use for the future. Adenovirus are double-stranded DNA viruses, with a high effeciency of delivery and expression of their genome in nuclei of dividing and non-dividing cells (Voplers & Kochanek, 2004). They are relatively large viral structures, with the capacity to carry constructs of up to 30 kB (Lyon et al., 2011). However, despite the fact that they are relatively cheap to produce in high titers and with a reasonably high purity, a major issue is that they evoke an immune response. As naturally occurring pathogens, patients are likely to have encountered them previously. Thus immune responses leading to destruction of cells containing adenovirus in the heart is a likely outcome. The latter factor also limits the time frame of therapeutic gene expression (Lyon et al., 2011). However, since work on gene therapy of the heart started with adenoviral vectors, the experience in use of this vector is high, and it is an excellent tool for basic science studies to evaluate the therapuetic potential of novel genes.
\n\t\t\t\t
Attempts are being made to reduce the immunogenicity of adenoviruses, removing the viral genome and viral proteins. The third generation of “gutless” adenovirus have low immunogenicity, and longer transgene expression (Chen et al., 1997). Direct myocardial delivery of gutless adenovirus resulted in less inflammation than the first generation virus, but the gene expression was not high and it was short-lasting (Fleury et al., 2004). Another still remaining problem with adenovirus in the heart is the affinity for other organs such as gastrointestinal tract, liver, respiratory tract, and muscle, causing side effects in clinical trials (Lavu et al., 20120, Lyon et al., 2011).
\n\t\t\t\t
Adenoassociated viruses (AAV) are currently without comparison the most suitable vectors for cardiovascular gene transfer. AAVs are not associated with any human pathology although 20-40% of all humans may have antibodies to them, making them attractive and safe for clinical treatment. AAVs exist in different seroforms, which have different affinity for the heart. The most recent serotyope, AAV9, is more cardiotropic than any other known virus and will transfect nearly 100% of all heart cells (Vandendriessche et al., 2007). AAV9 causes a sustained cardiac expression of the delivered gene, with little leakage to other organs (Bish et al., 2008, Inagaki et al., 2006, Zincarelli et al., 2008, Pacak et al., 2006). AAV1, 6, and 8 also have relatively high tropism to the heart, and since they have been around for a longer time, they have come further into clinical studies. AAV have been used for intracardiac, intravascular, and systemic gene delivery. Hitherto more than 20 clinical trials using AAV vectors have delivered the vectors to hundreds of patients without observing any adverse effects (Lyon et al. 2011, Leon et al. 2010). A major advantage of AAV9 is that a systemic approach to gene delivery can be used, thus avoiding some of the challenges of the other viral vectors.
\n\t\t\t\t
Retroviruses are RNA viruses which integrate into the host cell chromosome after enzymatic conversion to DNA. Retroviral vectors are modified to retain the part of the genome which is neccessary to initiate reverse transcription into the target cell, while the rest of the viral genome is removed (Lyon et al., 2011). Integration of virus into the cell requires cell division, which is why this vector can be suitable for therapies against endothelial or smooth muscle cells such as in avoiding atherosclerosis or restenosis, but less suitable for cardiomyocytes which have a low division rate. However, the insertion of retrovirus into the host genome may cause mutations, potentially leading to malignancies which can be passed on into the germline to offspring.
\n\t\t\t\t
Lentiviruses belong to the retroviridae family, and include vectors derived from the human immunodeficiency virus type I (HIV-1). Wild-type HIV-1 have an affinity for T-cell subpopulations, limiting their usability for cardiovascular purposes. Hybrid “pseudotyped” lentivirus have been produced to expand their tropism for other cell types. In the context of transfecting cardiomyocytes, lentiviral-based vectors are as effecient as adenoviruses, with transgene expression lasting longer (Yoshimitsu 2006). They can incorporate constructs up to 8 kB in size (Yoshimitsu). Lentivirurses are especially favoured in studies targeting transfection of endothelial cells or smooth muscle cells (Sakoda et al., 2007). The major obstacle towards a large-scale employment of lentivirus is currently uncertainties regarding safety. Modifications of the virus to avoid any risk of human disease are being performed, and may in the future lead to a larger therapeutic potential (Lyon et al. 2011).
\n\t\t\t
\n\t\t\t
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2.2. Intrapericardial gene delivery
\n\t\t\t\t
In theory, injection of DNA into the intrapericardial space may offer an environment which is relatively constant (no blood flow), and would be a relatively non-invasive approach for getting DNA to the heart. However, an intrapericardial injection can not lead to directed gene delivery, in the sense that there is no control over uptake in a specific type of cell or a specific area of the heart such as into the border zone of myocardial infarction. It is noteworthy that few publications exist using this option. Zhang and coworkers delivered adenoviral based LacZ into the pericardium of neonatal mice through a percutaneous puncture, and three days later found LacZ activity in the endocardium, epicardium, and myocardium (Zhang et al., 1999). However, the same regimen did not lead to wide-spread expression in adult hearts, in which hepatic transduction was found in high levels (Zhang et al., 1999). Using a transdiagfragmatic approach, Fromes et al. (1999) delivered adenoviral based β-galactodase intrapericardially in rats. Positive staining was found exclusively in pericardial cells. Mixing the virus with proteolytic enzymes increased transgene expression intramyocardially within a short time later, but the expression did not last, and there was leakage to other organs (Fromes et al., 1999). In the canine myocardium, March and coworkers (1999) delivered adenovirus based LacZ through a penetrating catheter. This lead to a pericardial-located activity of LacZ. The abscence of publications using this delivery approach for the last decade suggests that this is not a delivery route for the future.
\n\t\t\t\t
Figure 1.
The cartoon depicts possible routes of delivery of either stem cells or DNA with or without a vector to the heart. Systemic delivery is suitable only when DNA is ligated to a cardiotropic vector.
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\n\t\t\t\t
2.3. Intramyocardial gene delivery
\n\t\t\t\t
Gene delivery to the heart of either plasmid DNA or DNA ligated to a vector has been performed for decades both in experimental and in clinical trials (Lavu et al., 2010, Katz et al., 2010). Regardless of whether the injection is of plasmid DNA or DNA ligated to a vector, intramyocardial injections are invasive and do not have a clinical appeal. One can envision injection of DNA during open heart surgery when the heart is exposed anyway, or catheter-based delivery when a patient is undergoing invasive arterial procedures. However, except for open heart surgery with direct visualization the accuracy of such an approach is not high - if the intention is delivery of genes i.e. into an ischemic border zone to induce angiogenesis, it will be very difficult to control where exactly the injection site is in relation to where it would be wished to be. The approach has, however, given us invaluable research information on the therapeutic potential and limitations of genes thought to correct underlying pathologies. Many studies have used intramyocardial injections of DNA to induce angiogenesis. Delivery of the transcription factor GATA-4 ligated to an adenoviral vector before coronary artery ligation resulted in improved left ventricular function and reduced infarct size (Rysä et al., 2010). This was due to increased angiogenesis, decreased apoptosis, and mobilization of cardiac stem cells in GATA-4 treated hearts. AAV-based transfection with angiogenin in an in vivo infarction model reduced remodelling, induced angiogenesis, and attenuated cardiac dysfunction four weeks later (Zhao et al., 2006). Therapeutic use of AAV9-vascular endothelial growth factor-B is cardioprotective in canine pacing-induced dilated cardiomyopathy, but not due to formation of new vessels (Pepe et al., 2010). Delivery of adenoviral vector-ligated vascular endothelial growth factor B to rats with angiotensin II-induced hypertrophy leads to reduction of diastolic dysfunction, increasing capillary area but not density (Serpi et al., 2011). In a chronic ischemia model in rats, AAV2-based delivery of both vascular endothelial growth factor A and – B were protective (Zentilin et al., 2010). Vascular endothelial growth factor B was more protective than A, reducing apoptosis and remodelling and preserving heart function in the abscence of angiogenesis. Hepatocyte growth factor delivered by adenovirus into the myocardium following myocardial infarction preserved cardiac function, reduced remodelling and apoptosis, and induced angiogenesis (Jayasankar et al., 2003). Other studies have used antiinflammatory agents injected into the myocardium to combat ischemic heart disease and its consequences. Adenoviral-based expression of inhibitory kappa B-alpha in a rat infarction model improved heart function six weeks later (Trescher et al., 2004). AAV9 based delivery of heme oxygenase-1 into the myocardium before myocardial infarction had infarct reducing, anti-inflammatory, and antiapoptotic effects (Melo et al., 2002). Intramyocardial injection with inducible nitric oxide synthase ligated to adenovirus had an infarct-reducing effect both short-term and long-term (Li et al., 2006). This effect was mediated by inducible cyclooxygenase and nuclear factor kappa B (Liet al., 2007). Other cardioprotective genes in various models of heart disease are the inhibitor of matrix metalloproteinase TIMP-1 (Jayasankar 2004), the cell cycle regulator cyclin A2 (Woo et al., 2006), the regulator of organ development sonic hedgehog (Kusano et al., 2005); Notch1, regulator of cell proliferation and differentiation (Kratsios et al., 2010), the beta adrenoceptor receptor betaARKct (Rengo et al., 2009), and sphingosine kinase 1, a protective protein kinase (Duan et al., 2007). Thus, a major insight into possible therapeutic genes has been provided by this gene delivery route. Intramyocardial gene delivery is likely to remain a powerful research tool for testing the therapeutic potiential of genes in experimental models in the future. However, the future clinical gene therapies are unlikely to involve intramyocardial delivery at a large scale.
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2.4. Intravascular delivery
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Cardiac intravascular gene delivery has been performed through antegrade coronary artery delivery, non-selective intracoronary delivery (i.e. left ventricular injection), and retrogradely through the coronary sinus (Katz et al., 2010). Common for these approaches is the need to occlude the coronary circulation temporarily to allow virus to migrate into cells. The attractive aspect of this approach is the possibility of a minimally invasive delivery procedure through a catheter well within established clinical procedures (at least the antegrade technique) and the possibility to deliver into all four heart chambers. The first studies using coronary artery delivery resulted in very few transfected cells (Longeart et al., 2001, Hayase et al., 2005, Kaplitt et al., 1996). Later studies have refined delivery methods to some degree. With a recombinant AAV2 vector ligated to deliver enhanced green fluorescent protein, Kaspar and collegues (2005) used rats for indirect intracoronary delivery. Rats had transgene expression lasting up to 12 months, with a gradient of expression across the left ventricular wall, the epicardium expressing much more than the endocardium. There was evidence of AAV2 vector genome in liver and lungs of injected animals (Kaspar et al., 2005). Lai and coworkers (2004) delivered DNA encoding for adenylyl cyclase 6 ligated to an adenoviral vector into all three major coronary arteries of pigs with heart failure, using a vasodilator at the time of delivery, and compared with delivery of saline. Three weeks later left ventricular function was improved in the pigs recieving adenylyl cyclase 6. Gene expression in left ventricular biopsies evaluated with PCR was increased, although in which cells was not adressed (Lai et al., 2004). The success of intravascular gene delivery may depend on the target cell; if it is vascular, the chance of success may increase compared with a cardiac cell target. However, anything that enters the coronary circulation must enter the general circulation, reducing the clinical appeal of this approach. A special situation where this mode of delivery may be attractive is during open heart surgery with cardioplegic arrest.
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2.5. Gene therapy using non-viral vectors
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Although improvements are made in modifying viral vectors, reducing immunogenicity and increasing duration and amount of gene expression and narrowing the expression to target cells, researchers are travelling on alternative routes to deliver genes to the heart. Several non-viral techniques are used to improve the transfection efficacy of plasmids such as liposomes, polymers, electroporation, and nanotechnology (Holladay et al. 2010, Lukyanenko 2007). The status of these approaches are recently reviewed elsewhere (Holladay et al. 2010, Lukyanenko 2007).
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3. Cardioprotection by cell therapy
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Stem cell therapy for protecting hearts is a large topic. For readers particularly interested in the field, the recent reviews by Novotny et al. (2008), Beeres at al. (2008), and Atoui et al. (2008) are excellent. Stem cells are divided into committed and uncommitted cells, where the latter are the true stem cells in the sense that they are undifferenciated, capable of self-renewal, and multipotent (Novotny et al., 2008, Beeres et al., 2008, Atoui et al., 2008). These types of cells include multipotent bone marrow or adipose tissue derived mesenchymal stem cells and embryonic stem cells. Commited progenitor cells are more differentiated, and include endothelial progenitor cells, fetal cardiomyocytes, and autologous skeletal myoblasts. Experimental studies have successfully been able to induce neovascularization, increase cardiomyocyte survival, and improve postinfarct function through using cell transplantation. However, why it works is not completely clarified. Some investigators believe that stem cells dedifferentiate into cardiomyocytes, but not all studies confirm this finding (Silva et al., 2005, Cinnaird et al., 2004, Cocher et al., 2001, Murry et al., 2004). Possibly there is a fusion between the transplanted cells and the endogenous cardiomyocytes (Beeres et al., 2008). Possibly also the transplanted cells lead to recruitment of resident cardiac progenitor cells (Novotny et al., 2008, Beeres et al., 2008). Paracrine effects may be of importance. As transplanted cells have a short life span in their new environment, these effects will be transitory. Some suggested mechanisms of action are autocrine or paracrine release of cytokines and growth factors that will stimulate new vessel formation, inhibit apoptosis, rescue injured cardiomyocytes, and reduce pathologic remodelling. Recently, endogenous cardiac stem cells are reported to have even more promising potential for correcting cardiac pathologies. These cells are a large topic beyond the scope of this chapter (Bolli & Chaudrey, 2010).
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Therapeutic use of stem cells is now a clinical reality, but there is need for more laboratory work before this field can become useful in patients at a large scale. At the moment we do not know the optimal cell for delivery, the optimal amount of cells, or which route of delivery (as for gene therapy, intramyocardial, intravascular through artery or vein, pericardial and other approaches have all been performed) that will give the best outcome. Genetically modifed cells may act as transgene carriers and be used to deliver therapeutic targets to cardiac tissue. Transfected cells of different origins have been used in animal experiments to induce angiogenesis, increase contractility, decrease fibrosis, improve remodelling, and improve graft cell survival.
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Figure 2.
The advantages of using genetically engineered stem cells versus naive stem cells are illustrated. Naive stem cells do rescue myocardium, but the effects are much more pronounced when stem cells are genetically engineered.
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3.1. Genetically engineered stem cells as cardioprotective agents
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Based on the assumption that the major effect of stem cells is through their paracrine effects, quite a few works have focused on genetically engineered stem cells to produce angiogenic factors, with the perspective to both increase survival of the transplanted cell and to enhance the formation of new blood vessels in the infarcted heart. For instance, bone-marrow derived endothelial progenitor cells were expanded and transduced with AAV to overexpress insulin-like growth factor 1. Then the autologous cells were transplanted into the infarct area of rats (Sen et al., 2010). Three months later rats receiving insulin-like growth factor 1 transduced cells as opposed to LacZ-transduced cells had improved myocardial function, reduced apoptosis, increased number of capillaries, and increased cardiomyocyte proliferation in the infarct area. There was no dissemination of transduced cells into other organs (Sen et al., 2010). In a model of neointima formation in hypercholesterolemic rats, endothelial progenitor cells transduced to overexpress hepatocyte growth factor were delivered. The transduced cells homed to the vascular site of injury more than untreated cells, and this caused a decreased neointima formation and increased endothelialization (Song et al., 2009). Colony stimulating factor-1 was used to transfect primary autologous rat myoblasts, which were transplanted into the myocardium of rats with postinfarction heart failure (Aharinejad et al., 2008). Left ventricular function evaluated by echocardiography was improved in hearts of rats treated with with autologous colony stimulating factor myoblasts. This protection was not found after delivery of untransduced myoblasts or plasmid DNA encoding for colony stimulating factor. In a similar model myoblasts transduced with human growth factor were able to improve heart function, increase capillary density, and reduced apoptosis (Rong et al., 2008). Mesenchymal stem cells engineered to overexpress adrenomedullin transplanted after myocardial infarction improved cardiac function more than naive mesenchymal stem cells (Jo et al., 2007). The growth factor angiopoietin-1 in modified mesenchymal stem cells has reduced ischemic damage when injected shortly after ischemia in rat hearts (Sun et al., 2007). In pigs, mononuclear cells were extracted from peripheral blood and induced to overexpress vascular endothelial growth factor retrogradely delivered through the coronary sinus. The transduced cells induced angiogenesis and reduced postischemic ventricular dysfunction four weeks later (Hagikura et al., 2010). Vascular endothelial growth factor ligated to mesenchymal stem cells under the control of a hypoxia response element induced ischemia-responsive production of vascular endothelial growth factor when transplanted into the ischemic myocardium (Kim et al., 2010). This caused an increased retainment of genetically altered mesenchymal stem cells in the infarcted heart compared with naive cells, reduction of apoptosis, and reduced remodelling. Also hypoxia-regulated heme oxygenase-1 overexpressing mesenchymal stem cells transplanted into the infarcted ventricular wall improved survival of transplanted cells, improved heart function, and reduced cell death (Tang et al., 2005).
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Genetic modification of stem cells also improves cell survival and outcome of ischemia models when the gene in question is not considered to be a secretory molecule. Treatment of mesenchymal stem cells to overexpress connexin 43 followed by injection into infarcted myocardium improves left ventricular function and reduces cell death (Wang et al., 2010). Mesenchymal stem cells overexpressing heat shock protein of the 20 kDa family has similar beneficial effects (\n\t\t\t\t\t\tWang et al., 2009\n\t\t\t\t\t). In the latter study, the authors provide evidence that the protective effect could be through increased secretion of proteins, where vascular endothelial growth factor, insulin-like growth factor, and fibroblast growth factor were released from transfected cells. The authors speculate that the relased growth factors were due to a detected activation of the protein kinase Akt (\n\t\t\t\t\t\tWang et al., 2009\n\t\t\t\t\t). Indeed, mesenchymal stem cells overexpressing Akt itself transplanted into the ischemic myocardium improved left ventricular function, reduced infarct size, reduced apoptosis, increased mobilization of cardiac progenitor cells (c-kit+), and reduced collagen deposition (Mangi et al., 2003). The beneficial effects were dependent on the amount of transplanted cells. In a follow up study, the authors found that the mechanism for cardioprotection was not through stem cell fusion with cardiomyocytes, which occurred infrequently, and not due to differentiation of stem cells into cardiomyocytes (Noiseux et al. 2006). Another protein kinase associated with myocardial protection, Pim-1 kinase, was transfected into cardiac progenitor cells before injection into ischemic myocardium (Fischer et al., 2009). When animals were observed up to 32 weeks later, improved function and reduced infarct size was accompanied by increased survival of engrafted cells, increased vascularization, and increased number of c-kit+ cells (Fischer et al., 2009). Consequently, secondary secretory effects of genetic manipulation with a factor acting intracellularly is indicated. The antiapoptotic molecule Bcl2 has been used to transfect cardiomyoblasts (Kutcha et al., 2006) and mesenchymal stem cells (\n\t\t\t\t\t\tLi et al, 2007\n\t\t\t\t\t) before transplantation into infarcted myocardium, leading to improved function and survival of both engrafted cells and infarcted myocardium. Mesenchymal stem cells transfected with Bcl2 had an increased secretion of vascular endothelial growth factor in vitro, and an increased capillary density in vivo (\n\t\t\t\t\t\tLi et al., 2007\n\t\t\t\t\t). Finally, a few studies have used genes coding for antiinflammatory factors as enrichment of stem cells to improve survival of engrafted stem cells and the heart. Mesenchymal stem cells overexpressing the interleukin-18 binding protein, the naturally occurring inhibitor of the proinflammatory cytokine interleukin 18, improved cardioprotection more than that observed with unmodified stem cells (\n\t\t\t\t\t\tWang et al., 2009\n\t\t\t\t\t). The beneficial effects observed on heart function, remodelling, and infarct size could have been due to increased secretion of vascular endothelial growth factor and decreased interleukin 6 levels in hearts of animals treated with genetically modified cells. Mesenchymal stem cells have also been used to overexpress the chemokine receptors CCR1 and CXCR2 before intramyocardial injection into infarcted heart (Huang et al., 2010). Stem cells with overexpression of CCR1 had increased survival intramyocardially, which was accompanied by less cardiac remodelling, increased capillarization, and improved cardiac function in both acute and chronic (4 weeks) observation times. The effect was not found when cells were overexpressing CXCR2, which lead to similar findings as with naive mesenchymal stem cells (Huang et al., 2010).
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To conclude, we still have a long way to go to fully understand the mechanisms by which stem cells may protect hearts and which cell type and number that should be used for future therapies. However, it is well documented that genetic engineering of stem cells with both secretory factors and primarily intracellularly acting factors improve engrafted cell survival as well as survival of the myocardium. Many of the studies mentioned above using a primary intracellularly acting factor have documented secondary secretory effects.
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4. Cardiac gene therapy using a peripheral approach
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A downside with intracardiac delivery of either genes or genetically modified cells is the relative invasiveness of the method. It is possible to envision effects in the heart through a
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Figure 3.
The cartoon depicts the principle of remote gene therapy delivering plasmid DNA into the skeletal muscle, increasing nuclear uptake by electroporation, and achieving myocardial protection.
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peripheral approach, building upon the principle of general organ protection evoked by pre- or postconditioning (Przyklenk et al., 1993). Preconditioning is the observation that brief episodes of ischemia and reperfusion to an organ will protect the organ against a later ischemic event (Murry et al., 1986), while postconditioning is the observation that brief episodes of ischemia and reperfusion at the start of reperfusion will reduce organ damage (Zhao et al., 2003). It is shown that the protection afforded by these brief episodes of ischemia and reperfusion provide an universal organ protection termed remote preconditioning (Przyklenk et al., 1993). In a series of experiments we have delivered plasmid DNA encoding for hypoxia-inducible factor 1alpha (HIF-1α) into an easily accessible peripheral organ, the quadriceps skeletal muscle. Others have shown that the skeletal muscle may serve as an endocrine organ, stably secreting endocrine factors into the blood stream after delivery of plasmid DNA and enhancing nuclear uptake by electroporation (Mathisen et al., 1999). This gives a very local increase of gene expression, transfecting a few skeletal muscle fibers in the treated muscle and with no leakage to other organs (\n\t\t\t\t\tCzibik et al 2009\n\t\t\t\ta, 2009b). The skeletal muscle expression of HIF-1α lasted for 8 weeks (not investigated longer) (\n\t\t\t\t\tCzibik et al., 2009\n\t\t\t\ta). When hearts were isolated and Langendorff-perfused with global ischemia and reperfusion, they had improved function and reduced infarct size compared with hearts of mice which were not pretreated with HIF-1α (\n\t\t\t\t\tCzibik et al., 2009\n\t\t\t\ta). To attempt to unravel mechanisms underlying the beneficial effects of HIF-1α, a Taqman low density array of some 47 HIF-regulated genes was performed on samples of the transfected skeletal muscle one week later. Several genes encoding for growth factors were increased in the transfected muscle, among them insulin-like growth factor 2, heme oxygenase-1, adrenomedullin, and platelet derived growth factor B (\n\t\t\t\t\tCzibik et al. 2009\n\t\t\t\ta). When these factors were used to protect the cardiomyocyte cell line HL-1 cells against injury evoked by hydrogen peroxide, heme oxygenase-1 (HMOX-1) was beyond comparison most protective, with effects similar to that of HIF-1α (\n\t\t\t\t\tCzibik et al. 2009\n\t\t\t\tb).
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HMOX-1 is an inducible member of the heme oxygenase family of proteins, also consisting of the constitutive heme oxygenase-2 and the less well characterized heme oxygenase-3 (Durante et al., 2010, Wu et al., 2010). HMOX-1 expression is induced by its substrates: heme, oxidants, heavy metals, cytokines, growth factors, hemodynamic forces, gases, hypoxia, and hormones (Wu et al., 2011). Many transcription factors may be involved in its regulation. Some of them are HIF-1α, nuclear factor kappa B, activator protein 1, and nuclear factor E2-related factor (Wu et al., 2011). HMOX-1 catalyzes the degradation of heme into biliverdin, free iron, and carbon monoxide (Maines et al., 1986). Biliverdin is subsequently rapidly reduced to bilirubin by the enzyme biliverdin reductase. HMOX-1 is expressed in a plethora of cell types, including cardiac and vascular cells. Carbon monoxide, most known as a toxic gas, is recognized as an intracellular signalling molecule (Maines et al., 1986, Verma et al., 1993). Carbon monoxide has many cellular effects which have recently been reviewed elsewhere (Abraham & Kappas, 2008); in this context, it can be summarized that it may have antiinflammatory and antiapoptotic effects, lead to vasorelaxation, reduce lipid peroxidation and proliferation of vascular smooth muscle cells, and possibly induce angiogenesis. Bilirubin was shown to have antioxidant effects already in 1987 (Stocker et al.). Since then evidence supports that bilirubin regulates cellular redox states, reduces the formation of reactive oxygen species, and has antiinflammatory effects through decreasing the expression leukocyte adhesion molecules and neutrophil adhesion. Free iron may induce ferritin expression leading to iron sequestration. Thus, HMOX-1 through its downstream products is potentially very suitable for protection of cardiomyocytes.
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When the HIF-1α gene was delivered in vivo into skeletal muscle of rats, the expression of HMOX-1 was increased, accompanied by increased serum bilirubin (\n\t\t\t\t\tCzibik et al., 2009\n\t\t\t\tb, Czibik et al., 2011). When a HMOX-1 blocker was given together with plasmid DNA encoding for HIF-1α and the hearts isolated and perfused with induced global ischemia, the beneficial effect of gene therapy was abolished (\n\t\t\t\t\tCzibik et al., 2009\n\t\t\t\tb). Delivery of plasmid DNA endocing for HMOX-1 before isolated heart perfusion mimicked the beneficial effects of HIF-1α (\n\t\t\t\t\tCzibik et al.,2009\n\t\t\t\tb). Gene delivery of HIF-1α into the skeletal muscle protected the heart ex vivo, and in vitro, and was also evaluated to be highly cardioprotective in an in vivo model of cardiac ischemia-reperfusion with remodelling six weeks later (\n\t\t\t\t\tCzibik et al., 2009\n\t\t\t\ta, 2009b, 2011). Unfortunately, systemic delivery of HIF-1α induced a general angiogenesis evident as increased CD31 positive staining in the electroporated muscle with gene delivery, the contralateral muscle, and in the heart (\n\t\t\t\t\tCzibik et al., 2009\n\t\t\t\ta, 2009b, 2011). Downstream factors to hypoxia inducible factor may turn out to be cardioprotective without the unwanted side-effects. Delivery of plasmid DNA encoding for HMOX-1 into the skeletal muscle before in vivo infarction protects against postinfarct remodelling without causing angiogenesis (manuscript in progress). Thus, these promising results from mice experimental studies should now be tested in larger animals as a bridge to human therapy.
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5. Conclusion
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For the treatment of cardiovascular disease, gene therapy may become an alternative in the near future. Gene delivery through intravascular approaches, intramyocardial injection, and pericardial route have been tried using plasmid DNA, adeno-, retro-, lenti-, and adenoassociated viral vectors. Of the viral vectors, adenoassociated virus serotype 9 is the most promising, as it is cardiotropic and can be delivered systemically. Stem cells are another approach to novel therapies against ischemic heart disease. Stem cells can be delivered through the same routes as genes. At the moment the mechanism of stem cell-induced protection of the heart is not well understood - the cells tend to stay shortly in the myocardium, and to a low degree fuse with cardiomyocytes or differentiate into cardiomyocytes. Possibly paracrine effects of stem cells are the reason for cardioprotection. Genetic engineering of stem cells improves the therapeutic effect of transplanted cells, both when the engineering is for a secretory factor and when it is overexpressing a factor primarily working intracellularly, and secondarily secretory. Gene therapy of the heart can also be evoked through using the skeletal muscle as a site of gene transfer, where delivery of plasmid DNA encoding for both hypoxia-inducible factor 1 alpha and its downstream target heme oxygenase-1 protects cardiomyocytes in vivo, ex vivo, and in vitro.
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Acknowledgments
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Arkady Rutkovskiy, MD, is gratefully acknowledged for making illustrations. Jarle Vaage, MD, PhD, read and commented on the manuscript. Financial support was recieved by the Norwegian Health Association, The Norwegian Women\'s Public Health Association, and the University of Oslo.
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\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/17931.pdf",chapterXML:"https://mts.intechopen.com/source/xml/17931.xml",downloadPdfUrl:"/chapter/pdf-download/17931",previewPdfUrl:"/chapter/pdf-preview/17931",totalDownloads:1977,totalViews:117,totalCrossrefCites:1,totalDimensionsCites:1,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:63,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"October 20th 2010",dateReviewed:"April 21st 2011",datePrePublished:null,datePublished:"August 23rd 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/17931",risUrl:"/chapter/ris/17931",book:{id:"501",slug:"targets-in-gene-therapy"},signatures:"Guro Valen",authors:[{id:"28319",title:"Prof.",name:"Guro",middleName:null,surname:"Valen",fullName:"Guro Valen",slug:"guro-valen",email:"guro.valen@medisin.uio.no",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Gene therapy for myocardial protection",level:"1"},{id:"sec_2_2",title:"2.1. Viral vectors",level:"2"},{id:"sec_3_2",title:"2.2. Intrapericardial gene delivery",level:"2"},{id:"sec_4_2",title:"2.3. Intramyocardial gene delivery",level:"2"},{id:"sec_5_2",title:"2.4. Intravascular delivery",level:"2"},{id:"sec_6_2",title:"2.5. Gene therapy using non-viral vectors",level:"2"},{id:"sec_8",title:"3. Cardioprotection by cell therapy ",level:"1"},{id:"sec_8_2",title:"3.1. Genetically engineered stem cells as cardioprotective agents",level:"2"},{id:"sec_10",title:"4. Cardiac gene therapy using a peripheral approach",level:"1"},{id:"sec_11",title:"5. Conclusion",level:"1"},{id:"sec_12",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbraham\n\t\t\t\t\t\t\tN. 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New Biol\n\t\t\t\t\t3\n\t\t\t\t\t71\n\t\t\t\t\t81 .\n\t\t\t'},{id:"B3",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAharinejad\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbraham\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPaulus\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZins\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHofman\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMichilits\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGyöngyösi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMacfelda\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLucas\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTreschner\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrimm\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStanley\n\t\t\t\t\t\t\tE. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Colony-stimulating factor-1 transfection of myoblasts improves the repair of failing myocardium following autologous myoblast transplantation. Cardiovasc Res\n\t\t\t\t\t79\n\t\t\t\t\t395\n\t\t\t\t\t404 .\n\t\t\t'},{id:"B4",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAtoui\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShum-Tim\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChiu\n\t\t\t\t\t\t\tR. C. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Myocardial regenerative therapy: immunologic basis for the potential universal donor cells. Ann Thorac Surg\n\t\t\t\t\t86\n\t\t\t\t\t327\n\t\t\t\t\t334 .\n\t\t\t'},{id:"B5",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarr\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarroll\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKalynych\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTripathy\n\t\t\t\t\t\t\tS. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKozarsky\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilson\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeiden\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1994 Efficient catheter-mediated gene transfer into the heart using replication-deficient adenovirus. Gene Ther\n\t\t\t\t\t1\n\t\t\t\t\t51\n\t\t\t\t\t58 .\n\t\t\t'},{id:"B6",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeeres\n\t\t\t\t\t\t\tS. L. M. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAtsma\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvan Ramshorst\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchalij\n\t\t\t\t\t\t\tM. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBax\n\t\t\t\t\t\t\tJ. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Cell therapy for ischemic heart disease. Heart 94\n\t\t\t\t\t1214\n\t\t\t\t\t1226 .\n\t\t\t'},{id:"B7",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBish\n\t\t\t\t\t\t\tL. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorine\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSleeper\n\t\t\t\t\t\t\tM. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSanmiguel\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilson\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSweeney\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 AAV9 provides global cardiac gene transfer superior to AAV1, AAV6, AAV7, and AAV8 in the mouse and rat. Hum Gene Ther\n\t\t\t\t\t19\n\t\t\t\t\t1359\n\t\t\t\t\t1368 .\n\t\t\t'},{id:"B8",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBolli\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChaudhry\n\t\t\t\t\t\t\tH. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Molecular physiology of cardiac regeneration. Ann NY Acad Sci\n\t\t\t\t\t1211\n\t\t\t\t\t113\n\t\t\t\t\t126 .\n\t\t\t'},{id:"B9",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tButtrick\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKass\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKitsis\n\t\t\t\t\t\t\tR. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaplan\n\t\t\t\t\t\t\tM. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeinwand\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1992 Behaviour of genes directly injected into the rat heart in vivo. Circ Res\n\t\t\t\t\t3\n\t\t\t\t\t193\n\t\t\t\t\t198 .,\n\t\t\t'},{id:"B10",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tH. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMack\n\t\t\t\t\t\t\tL. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKelly\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOntell\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKochanek\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClemens\n\t\t\t\t\t\t\tP. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1997 Persistance in muscle of an adenoviral vector that lacks all viral genes. Proc Nat Acad Sci USA\n\t\t\t\t\t94\n\t\t\t\t\t1654\n\t\t\t\t\t1650 .\n\t\t\t'},{id:"B11",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCzibik\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartinov\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRuusalepp\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSagave\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSkare\n\t\t\t\t\t\t\tØ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tValen\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009 In vivo remote delivery of DNA encoding for hypoxia-inducible factor 1 alpha reduces myocardial infarct size. Clinical and Translational Science\n\t\t\t\t\t1\n\t\t\t\t\t33\n\t\t\t\t\t40 .\n\t\t\t'},{id:"B12",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCzibik\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSagave\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartinov\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshaq\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSohl\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSefland\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarlsen\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlomhoff\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFarnebo\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tValen\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009 Cardioprotection by hypoxia-inducible factor 1 alpha transfection in skeletal muscle is critically dependent on heme oxygenase activity in mice. Cardiovasc Res\n\t\t\t\t\t82\n\t\t\t\t\t107\n\t\t\t\t\t114 .\n\t\t\t'},{id:"B13",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCzibik\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGravning\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartinov\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshaq\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAttramadal\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tValen\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011 Remote delivery of DNA encoding for hypoxia-inducible factor 1 alpha is protective against in vivo myocardial ischemia-reperfusion injury. Life Sciences\n\t\t\t\t\t16\n\t\t\t\t\t71\n\t\t\t\t\t78 .\n\t\t\t'},{id:"B14",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDuan\n\t\t\t\t\t\t\tH. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tH. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLu\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tC. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tL. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007 Adenoviral gene transfer of sphingosine kinase 1 protects heart against ischemia/reperfusion-induced injury and attenuates its postischemic failure. Hum Gene Ther\n\t\t\t\t\t18\n\t\t\t\t\t1119\n\t\t\t\t\t1128 .\n\t\t\t'},{id:"B15",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDurante\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Targeting heme oxygenase-1 in vascular disease. Current Drug Targets\n\t\t\t\t\t11\n\t\t\t\t\t1504\n\t\t\t\t\t1516 .\n\t\t\t'},{id:"B16",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFechner\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSipo\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWesternmann\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPinkert\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSuckau\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKurreck\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZeichhardt\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMüller\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVetter\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tErdmann\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTschope\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoller\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Cardiac-targeted RNA interference mediated by an AAV9 vector improves cardiac function in coxackievirus B3 cardiomyopathy. J Mol Med\n\t\t\t\t\t86\n\t\t\t\t\t987\n\t\t\t\t\t997 .\n\t\t\t'},{id:"B17",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFischer\n\t\t\t\t\t\t\tK. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCottage\n\t\t\t\t\t\t\tC. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDin\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGude\n\t\t\t\t\t\t\tN. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAvitabile\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQuijada\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCollins\n\t\t\t\t\t\t\tB. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFransioli\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSussman\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009 Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase. Circulation\n\t\t\t\t\t120\n\t\t\t\t\t2077\n\t\t\t\t\t2087 .\n\t\t\t'},{id:"B18",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFleury\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDriscoli\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSimeoni\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDudler\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon\n\t\t\t\t\t\t\tSegesser. L. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKappenberger\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVassalli\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Helper-dependent adenovirus vectors devoid of all viral genes cause less myocardial inflammation compared with first-generation adenovirus vectors. Basic Res Cardiol\n\t\t\t\t\t99\n\t\t\t\t\t247\n\t\t\t\t\t258 .\n\t\t\t'},{id:"B19",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrench\n\t\t\t\t\t\t\tB. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMazur\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGeske\n\t\t\t\t\t\t\tR. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBolli\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1994 Direct in vivo transfer to porcine myocardium using replication-deficient adenoviral vectors. Circulation\n\t\t\t\t\t90\n\t\t\t\t\t2412\n\t\t\t\t\t2424 .\n\t\t\t'},{id:"B20",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFromes\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSalmon\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCollin\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRouche\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHagege\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchwartz\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFiszman\n\t\t\t\t\t\t\tM. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999 Gene delivery to the myocardium by intraperitoneal injection. Gene Ther\n\t\t\t\t\t6\n\t\t\t\t\t683\n\t\t\t\t\t688 .\n\t\t\t'},{id:"B21",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuzman\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLemarchand\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCrystal\n\t\t\t\t\t\t\tR. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEpstein\n\t\t\t\t\t\t\tS. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFinkel\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1993 Efficient gene transfer into myocardium by dierct injection of adenovirus vectors. Circ Res\n\t\t\t\t\t73\n\t\t\t\t\t1202\n\t\t\t\t\t1207 .\n\t\t\t'},{id:"B22",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHagikura\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFukuda\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYokoyama\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYuxin\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKusumi\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIkeda\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKunimoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakayama\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJumabay\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMitsumata\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaito\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHirayama\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMugishima\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Low invasive angiogenic therapy for myocardial infarction by retrograde transplantation of mononuclear cells expressing the VEGF gene. Int J Cardiol\n\t\t\t\t\t142\n\t\t\t\t\t56\n\t\t\t\t\t64 .\n\t\t\t'},{id:"B23",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHayase\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tdel Monte\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKawase\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMac\n\t\t\t\t\t\t\tNeill. B. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Gregor\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoneyama\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHoshino\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsuji\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Grand\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGwathmey\n\t\t\t\t\t\t\tJ. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrangioni\n\t\t\t\t\t\t\tJ. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHajjar\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005 Catheter-based antegrade intracoronary viral gene delivery with coronary Venous blockade. Am J Physiol 288:H2995 -H3000.\n\t\t\t'},{id:"B24",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuo\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNi\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDeb\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZghang\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMirotsou\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPratt\n\t\t\t\t\t\t\tR. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDzau\n\t\t\t\t\t\t\tV. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engratfment, and capillary density in the injured myocardium. Circ Res\n\t\t\t\t\t106\n\t\t\t\t\t1753\n\t\t\t\t\t1762 .\n\t\t\t'},{id:"B25",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tInagaki\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFuess\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStorm\n\t\t\t\t\t\t\tT. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGibson\n\t\t\t\t\t\t\tG. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMctiernen\n\t\t\t\t\t\t\tC. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKay\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakai\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006 Robust systemic transduction with AAV9 vectors in mice; Efficient global cardiac gene transfer superior to that of AAV8. Molecular Therapy\n\t\t\t\t\t14\n\t\t\t\t\t45\n\t\t\t\t\t53 .\n\t\t\t'},{id:"B26",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIsner\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002 Myocardial gene therapy. Nature\n\t\t\t\t\t415\n\t\t\t\t\t234\n\t\t\t\t\t239 .\n\t\t\t'},{id:"B27",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJayasankar\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWoo\n\t\t\t\t\t\t\tY. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBish\n\t\t\t\t\t\t\tL. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPirolli\n\t\t\t\t\t\t\tT. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChatterjee\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBerry\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBurdick\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGardner\n\t\t\t\t\t\t\tT. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSweeney\n\t\t\t\t\t\t\tH. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003 Gene transfer of hepatocyte growth factor attenuates postinfarction heart failure. Circulation 108 Supl1:I1230\n\t\t\t\t\t1236 .\n\t\t\t'},{id:"B28",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJayasankar\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWoo\n\t\t\t\t\t\t\tY. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBish\n\t\t\t\t\t\t\tL. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPirolli\n\t\t\t\t\t\t\tT. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBerry\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBurdick\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBhalla\n\t\t\t\t\t\t\tR. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSharma\n\t\t\t\t\t\t\tR. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGardner\n\t\t\t\t\t\t\tT. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSweeney\n\t\t\t\t\t\t\tH. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Inhibition of matrix metalloproteinase activity by TIMP-1 gene transfer effectively treats ischemic cardiomyopathy. Circulation 110 Supl1:I1180\n\t\t\t\t\t1186 .\n\t\t\t'},{id:"B29",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJo\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNagaya\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiyhara\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKataoka\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarada-Shiba\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKangawa\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTabata\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007 Transplantation of genetically engineered mesenchymal stem cells improves cardiac function in rats with myocardial infarction: benefit of a nonviral vector, cationized dextran. Tissue Eng\n\t\t\t\t\t13\n\t\t\t\t\t313\n\t\t\t\t\t322 .\n\t\t\t'},{id:"B30",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaplitt\n\t\t\t\t\t\t\tM. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSamulski\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOjamaa\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKlein\n\t\t\t\t\t\t\tI. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMakimura\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaplitt\n\t\t\t\t\t\t\tM. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStrumpf\n\t\t\t\t\t\t\tR. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDiethrich\n\t\t\t\t\t\t\tE. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1996 Long-term gene transfer in porcine myocardium after coronary infusion of an adeno-associated virus vector. Ann Thorac Surg 62-1669-1676.\n\t\t\t'},{id:"B31",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaspar\n\t\t\t\t\t\t\tB. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoth\n\t\t\t\t\t\t\tD. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLai\n\t\t\t\t\t\t\tN. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDrumm\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tErickson\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Kirnan\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHammond\n\t\t\t\t\t\t\tH. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005 Myocardial gene transfer and long-term expression following intracoronary delivery of adeno-associated virus. J Gene Medicine\n\t\t\t\t\t7\n\t\t\t\t\t316\n\t\t\t\t\t324 .\n\t\t\t'},{id:"B32",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKatz\n\t\t\t\t\t\t\tM. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSwain\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTomasulo\n\t\t\t\t\t\t\tC. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSumaroka\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFargnoli\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBridges\n\t\t\t\t\t\t\tC. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011 Current strategies for myocardial gene delivery. J Mol Cell Cardiol epub ahead of print\n\t\t\t'},{id:"B33",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKim\n\t\t\t\t\t\t\tH. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoon\n\t\t\t\t\t\t\tH. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKim\n\t\t\t\t\t\t\tH. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHwang\n\t\t\t\t\t\t\tK. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChoi\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011 Hypoxia-inducible vascular endothelial growth factor-engineered mesenchymal stem cells prevent myocardial ischemic injury. Molecular Therapy\n\t\t\t\t\t19\n\t\t\t\t\t741\n\t\t\t\t\t750 .\n\t\t\t'},{id:"B34",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKinnaird\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStabile\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBurnett\n\t\t\t\t\t\t\tM. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShou\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tC. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarr\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFuchs\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEpstein\n\t\t\t\t\t\t\tS. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation\n\t\t\t\t\t109\n\t\t\t\t\t1543\n\t\t\t\t\t1549 .\n\t\t\t'},{id:"B35",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKochner\n\t\t\t\t\t\t\tA. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchuster\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSzaboics\n\t\t\t\t\t\t\tM. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001 Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7\n\t\t\t\t\t430\n\t\t\t\t\t436 .\n\t\t\t'},{id:"B36",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKratsios\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCatela\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSalimova\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuth\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBerno\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosenthal\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMourkioti\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Distinct roles for cell-autonomous Notch signalling in cardiomyocytes of the embryonic and adult heart. Circ Res\n\t\t\t\t\t106\n\t\t\t\t\t559\n\t\t\t\t\t572 .\n\t\t\t'},{id:"B37",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKusano\n\t\t\t\t\t\t\tK. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPola\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMurayama\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCurry\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKawamoto\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIwakura\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShintani\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAsai\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTkebuchava\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThorne\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakenaka\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAikawa\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoukassian\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon\n\t\t\t\t\t\t\tSamson. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHamada\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoon\n\t\t\t\t\t\t\tY. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSilver\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEaton\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMa\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeyd\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKearney\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMunger\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPorter\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKishore\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLosordo\n\t\t\t\t\t\t\tD. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005 Sonic hedgehog myocardial gene therapy; tissue repair through transient reconstitution of embryonic signalling. Nat Med\n\t\t\t\t\t11\n\t\t\t\t\t1197\n\t\t\t\t\t1204 .\n\t\t\t'},{id:"B38",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKutschka\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKofidis\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tI. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon\n\t\t\t\t\t\t\tDegenfeld. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZwierzchoniewska\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHoyt\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLebl\n\t\t\t\t\t\t\tD. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHendry\n\t\t\t\t\t\t\tS. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSheikh\n\t\t\t\t\t\t\tA. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCooke\n\t\t\t\t\t\t\tD. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tConnolly\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlau\n\t\t\t\t\t\t\tH. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGambhir\n\t\t\t\t\t\t\tS. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRobbins\n\t\t\t\t\t\t\tR. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006 Adenoviral human BCL-2 transgene expression attenuates early donorcell death after cardiomyoblast transplantation into ischemic rat hearts. Circulation\n\t\t\t\t\t114\n\t\t\t\t\t174\n\t\t\t\t\t178 .\n\t\t\t'},{id:"B39",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLai\n\t\t\t\t\t\t\tN. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoth\n\t\t\t\t\t\t\tD. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tM. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTang\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDalton\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLai\n\t\t\t\t\t\t\tY. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSpellman\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClopton\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHammond\n\t\t\t\t\t\t\tH. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure. Circulation 110\n\t\t\t\t\t330\n\t\t\t\t\t336 .\n\t\t\t'},{id:"B40",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLavu\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGundewar\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLefer\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011 Gene therapy for ischemic heart disease. J Mol Cell Cardiol\n\t\t\t\t\t50\n\t\t\t\t\t742\n\t\t\t\t\t750 .\n\t\t\t'},{id:"B41",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tQ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuo\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTan\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStein\n\t\t\t\t\t\t\tA. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDawn\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tW. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSiddiqui\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTiwari\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBolli\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006 Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences. Am J Physiol 290:H584\n\t\t\t\t\t589 .\n\t\t\t'},{id:"B42",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tQ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuo\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTan\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOu\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tW. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSturza\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDawn\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHunt\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCui\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBolli\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007 Cardioprotection afforded by inducible nitric oxide synthase gene therapy is mediated by cyclooxygenase-2 via a nuclear factor-kappaB dependent pathway. Circulation 116\n\t\t\t\t\t1577\n\t\t\t\t\t1584 .\n\t\t\t'},{id:"B43",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMa\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOng\n\t\t\t\t\t\t\tL. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNesselmann\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKlopsch\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLadilov\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFurlani\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPiechaczek\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoebius\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLützow\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLendlein\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStamm\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tR. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSteinhoff\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007 Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells\n\t\t\t\t\t8\n\t\t\t\t\t2118\n\t\t\t\t\t2127 .\n\t\t\t'},{id:"B44",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParmacek\n\t\t\t\t\t\t\tM. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorle\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBolling\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeiden\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1990 Expression of recombinant genes in myocardium in vivo after direct injection of DNA. Circulation\n\t\t\t\t\t82\n\t\t\t\t\t2217\n\t\t\t\t\t2221 .\n\t\t\t'},{id:"B45",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLogeart\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHatem\n\t\t\t\t\t\t\tS. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeimburger\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoux\n\t\t\t\t\t\t\tA. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMichel\n\t\t\t\t\t\t\tJ. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMercadier\n\t\t\t\t\t\t\tJ. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001 How to optimize in vivo gene transfer to cardiac myocytes: mechanical or pharmacological procedures? Hum Gene Ther\n\t\t\t\t\t12\n\t\t\t\t\t1601\n\t\t\t\t\t1610 .\n\t\t\t'},{id:"B46",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLyon\n\t\t\t\t\t\t\tA. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSato\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHajjar\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSamulski\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarding\n\t\t\t\t\t\t\tS. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Gene therapy: Targeting the myocardium. Heart\n\t\t\t\t\t94\n\t\t\t\t\t89\n\t\t\t\t\t99 .\n\t\t\t'},{id:"B47",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaines\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTrakshel\n\t\t\t\t\t\t\tG. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKutty\n\t\t\t\t\t\t\tR. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1986 Characterization of two constitutive forms of rat liver microsomal heme oxygenase; only one molecular species of the enzyme is inducible. J Biol Chem\n\t\t\t\t\t261\n\t\t\t\t\t411\n\t\t\t\t\t419 .\n\t\t\t'},{id:"B48",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMagovern\n\t\t\t\t\t\t\tC. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMack\n\t\t\t\t\t\t\tC. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHahn\n\t\t\t\t\t\t\tR. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKo\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIsom\n\t\t\t\t\t\t\tO. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCrystal\n\t\t\t\t\t\t\tR. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosengart\n\t\t\t\t\t\t\tT. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1996 Direct in vivo gene transfer to canine myocardioum using a replication-deficient adenoviral vector. Ann Thorac Surg\n\t\t\t\t\t62\n\t\t\t\t\t425\n\t\t\t\t\t433 .\n\t\t\t'},{id:"B49",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMangi\n\t\t\t\t\t\t\tA. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoiseux\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKong\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHe\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRezvani\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIngwall\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDzau\n\t\t\t\t\t\t\tV. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003 Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med\n\t\t\t\t\t9\n\t\t\t\t\t1195\n\t\t\t\t\t1201 .\n\t\t\t'},{id:"B50",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarch\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\tK. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWoody\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMehdi\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZipes\n\t\t\t\t\t\t\tD. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBradtly\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTrapnell\n\t\t\t\t\t\t\tB. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999 Efficient in vivo catheter-based pericardial gene transfer mediated by adenoviral vectors. Clin Cardiol\n\t\t\t\t\t22\n\t\t\t\t\t123\n\t\t\t\t\t129 .\n\t\t\t'},{id:"B51",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMathiesen\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLømo\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999 Electropermeabilization of skeletal muscle enhances gene transfer in vivo. Gene Ther\n\t\t\t\t\t6\n\t\t\t\t\t508\n\t\t\t\t\t14 .\n\t\t\t'},{id:"B52",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMelo\n\t\t\t\t\t\t\tL. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAgrawal\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRezvani\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMangi\n\t\t\t\t\t\t\tA. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEhsan\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGriese\n\t\t\t\t\t\t\tD. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDell’Acqua\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMann\n\t\t\t\t\t\t\tM. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOyama\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYet\n\t\t\t\t\t\t\tS. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLayne\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPerrella\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDzau\n\t\t\t\t\t\t\tV. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002 Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene. Circulation\n\t\t\t\t\t105\n\t\t\t\t\t602\n\t\t\t\t\t607 .\n\t\t\t'},{id:"B53",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMurry\n\t\t\t\t\t\t\tC. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJennings\n\t\t\t\t\t\t\tR. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReimer\n\t\t\t\t\t\t\tK. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1986 Preconditioning with ischemia: a delay in lethal injury in ischemic myocardium. Circulation\n\t\t\t\t\t74\n\t\t\t\t\t1124\n\t\t\t\t\t1136 .\n\t\t\t'},{id:"B54",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMurry\n\t\t\t\t\t\t\tC. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSoonpaa\n\t\t\t\t\t\t\tM. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReinecke\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakajima\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRubart\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPasumarthi\n\t\t\t\t\t\t\tK. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVirag\n\t\t\t\t\t\t\tJ. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBertelmez\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoppa\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBradford\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDowell\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilliams\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tField\n\t\t\t\t\t\t\tL. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Haematopoietic stem cells do not transdifferentiate into cardiac myoblasts in myocardial infarcts. Nature\n\t\t\t\t\t428\n\t\t\t\t\t664\n\t\t\t\t\t668 .\n\t\t\t'},{id:"B55",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoiseux\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGnecchi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLopez-Ilasaca\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSolomon\n\t\t\t\t\t\t\tS. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDeb\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDzau\n\t\t\t\t\t\t\tV. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPratt\n\t\t\t\t\t\t\tR. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006 Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther\n\t\t\t\t\t14\n\t\t\t\t\t840\n\t\t\t\t\t850 .\n\t\t\t'},{id:"B56",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNovotny\n\t\t\t\t\t\t\tN. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRay\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarkel\n\t\t\t\t\t\t\tT. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCrisostomo\n\t\t\t\t\t\t\tP. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeldrum\n\t\t\t\t\t\t\tD. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Stem cell therapy in myocardial repair and remodelling. J Am Coll Surg\n\t\t\t\t\t207\n\t\t\t\t\t423\n\t\t\t\t\t434 .\n\t\t\t'},{id:"B57",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPacak\n\t\t\t\t\t\t\tC. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMah\n\t\t\t\t\t\t\tC. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThattaliyath\n\t\t\t\t\t\t\tB. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tConlon\n\t\t\t\t\t\t\tT. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLewis\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCloutier\n\t\t\t\t\t\t\tD. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZolotukhin\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTarantal\n\t\t\t\t\t\t\tA. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tByrne\n\t\t\t\t\t\t\tB. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006 Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ Res 99:e3 -e9.\n\t\t\t'},{id:"B58",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPepe\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMamdani\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZentilin\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCsiszar\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQanud\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZacchigna\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUngvari\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPuliqadda\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoimas\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEdwards\n\t\t\t\t\t\t\tJ. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHintze\n\t\t\t\t\t\t\tT. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGiacca\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRecchia\n\t\t\t\t\t\t\tF. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Intramyocardial VEGF-B167 gene delivery delays the progression towards congestive failure in dogs with pacing-induced dilated cardiomyopathy. Circ Res\n\t\t\t\t\t106\n\t\t\t\t\t1893\n\t\t\t\t\t1903 .\n\t\t\t'},{id:"B59",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPrzyklenk\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBauer\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOvize\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKloner\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWhittaker\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1993 Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation\n\t\t\t\t\t87\n\t\t\t\t\t893\n\t\t\t\t\t899 .\n\t\t\t'},{id:"B60",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRengo\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLymperopoulus\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZincarelli\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDonniacuo\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSoltys\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRabinowitz\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoch\n\t\t\t\t\t\t\tW. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009 Myocardial adeno-associated virus serotype 6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation\n\t\t\t\t\t119\n\t\t\t\t\t89\n\t\t\t\t\t98 .\n\t\t\t'},{id:"B61",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRong\n\t\t\t\t\t\t\tS. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLu\n\t\t\t\t\t\t\tY. X.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tX. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tY. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChang\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tY. Q.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tQ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tY. Z.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMi\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Effects of transplanted myoblasts transfected with human growth hormone gene on improvement of ventricular function of rats. Chin Med J\n\t\t\t\t\t121\n\t\t\t\t\t347\n\t\t\t\t\t354 .\n\t\t\t'},{id:"B62",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRysä\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTenhunen\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSerpi\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSoini\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNemer\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeskinen\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRuskoaho\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 GATA-4 is an angigenic survival factor of the infarcted heart. Circ Heart Fail\n\t\t\t\t\t3\n\t\t\t\t\t440\n\t\t\t\t\t450 .\n\t\t\t'},{id:"B63",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSakoda\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKasahara\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKedes\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOhyanagi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007 Lentiviral vector-mediated gene transfer to endothelial cells compared with adenoviral and retroviral vectors. Prep Biochem Biotechnol\n\t\t\t\t\t37\n\t\t\t\t\t1\n\t\t\t\t\t11 .\n\t\t\t'},{id:"B64",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSemenza\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 O2-regulated gene expression: transcriptional control of cardio-respiratory physiology by HIF-1. J Appl Physiol\n\t\t\t\t\t96\n\t\t\t\t\t1173\n\t\t\t\t\t1177 .\n\t\t\t'},{id:"B65",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSen\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMerchan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDean\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGavin\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSilver\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTkebuchava\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoon\n\t\t\t\t\t\t\tY. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRasko\n\t\t\t\t\t\t\tJ. E. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAikawa\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Autologous transplantation of endothelial progenitor cells genetically modified by adeno-associated viral vector delivering insulin-like growth factor-1 gene after myocardial infarction. Human Gene Therapy 21;1327\n\t\t\t\t\t1334 .\n\t\t\t'},{id:"B66",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSerpi\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTolonen\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuusko\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRysä\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTenhunen\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYlä-Herttuala\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRuskoaho\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011 Vascular endothelial growth factor-B gene transfer prevents angiotensin II-induced diastolic dysfunction via proliferation and capillary dilatation in rats. Cardiovasc Res 89\n\t\t\t\t\t204\n\t\t\t\t\t213 .\n\t\t\t'},{id:"B67",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSilva\n\t\t\t\t\t\t\tG. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLivotsky\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAssad\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSousa\n\t\t\t\t\t\t\tA. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartin\n\t\t\t\t\t\t\tB. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVela\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCoulter\n\t\t\t\t\t\t\tS. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOber\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVaughn\n\t\t\t\t\t\t\tW. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBranco\n\t\t\t\t\t\t\tR. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOliveira\n\t\t\t\t\t\t\tE. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHe\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGeng\n\t\t\t\t\t\t\tY. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWillerson\n\t\t\t\t\t\t\tJ. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPerin\n\t\t\t\t\t\t\tE. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005 Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation\n\t\t\t\t\t111\n\t\t\t\t\t150\n\t\t\t\t\t156 .\n\t\t\t'},{id:"B68",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSong\n\t\t\t\t\t\t\tM. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYu\n\t\t\t\t\t\t\tX. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tG. X.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhao\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009 Transfection of HGF gene enhances endothelial progenitor cell (EPC) function and improves EPC transplant efficiency for balloon-induced arterial injury in hypercholesterolemic rats. Vascul Pharmacol\n\t\t\t\t\t51\n\t\t\t\t\t205\n\t\t\t\t\t213 .\n\t\t\t'},{id:"B69",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSuckau\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFechner\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChemaly\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKrohn\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHadri\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKockskämper\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWesterman\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBisping\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLy\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKawase\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiang\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSipo\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVetter\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeger\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKurreck\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tErdmann\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTschope\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPieske\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLebeche\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchultheiss\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHajjar\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoller\n\t\t\t\t\t\t\tW. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009 Long-term cardiac-targeted RNA interference for the teratment of heart failure restores cardiac function and reduces pathological hypertrophy. Circulation\n\t\t\t\t\t119\n\t\t\t\t\t1241\n\t\t\t\t\t1252 .\n\t\t\t'},{id:"B70",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStocker\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamamoto\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Donagh\n\t\t\t\t\t\t\tA. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGlazer\n\t\t\t\t\t\t\tA. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmes\n\t\t\t\t\t\t\tB. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1987 Bilirubin is an antioxidant of possible physiological importance. Science\n\t\t\t\t\t235\n\t\t\t\t\t1043\n\t\t\t\t\t1046 .\n\t\t\t'},{id:"B71",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSun\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCui\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFeng\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMao\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKangtao\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhou\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007 Mesenchymal stem cells modified with angiopoietin-1 improve remodelling in a rat model of acute myocardial infarction. Biochem Biophys Res Commun\n\t\t\t\t\t357\n\t\t\t\t\t779\n\t\t\t\t\t784 .\n\t\t\t'},{id:"B72",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSvensson\n\t\t\t\t\t\t\tE. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarshall\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWoodard\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJiang\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChu\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeiden\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999 Efficient and stable transduction of cardiomyocytes after intramyocardial injection or intracoronary perfusion with recombinant adeno-associated virus vectors. Circulation\n\t\t\t\t\t99\n\t\t\t\t\t201\n\t\t\t\t\t205 .\n\t\t\t'},{id:"B73",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTang\n\t\t\t\t\t\t\tY. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tY. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQian\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShen\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPhillips\n\t\t\t\t\t\t\tM. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005 Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. J Am Coll Cardiol 46\n\t\t\t\t\t1339\n\t\t\t\t\t1350 .\n\t\t\t'},{id:"B74",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTomiyasu\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOda\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNomura\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSatoh\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFushiki\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tImanishi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKondo\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMazda\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000 Direct intracardiomuscular transfer of b2-adrenergic receptor gene augments cardiac output in cardiomyopathic hamsters. Gene Ther\n\t\t\t\t\t7\n\t\t\t\t\t2087\n\t\t\t\t\t2093 .\n\t\t\t'},{id:"B75",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTreschner\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBernecker\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFellner\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGyöngösi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKrieger\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDemartin\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWolner\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPodesser\n\t\t\t\t\t\t\tB. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Adenovirus-mediated overexpression of inhibitor kappa B-alpha attenuates postinfarct remdoeling in the rat heart. Eur J Cardiothorac Surg\n\t\t\t\t\t26\n\t\t\t\t\t960\n\t\t\t\t\t967 .\n\t\t\t'},{id:"B76",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVerma\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHirsch\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGlatt\n\t\t\t\t\t\t\tC. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRonnett\n\t\t\t\t\t\t\tG. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSnyder\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1993 Carbon monoxide: a putitative neural messenger. Science\n\t\t\t\t\t259\n\t\t\t\t\t381\n\t\t\t\t\t384 .\n\t\t\t'},{id:"B77",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVinge\n\t\t\t\t\t\t\tL. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRaake\n\t\t\t\t\t\t\tP. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoch\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Gene therapy in heart failure. Circ Res\n\t\t\t\t\t102\n\t\t\t\t\t1458\n\t\t\t\t\t1470 .\n\t\t\t'},{id:"B78",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVolpers\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKochanek\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Adenoviral vectors for gene transfer and therapy. J Gen Med 6(suppl 1):S164 -S171).\n\t\t\t'},{id:"B79",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWand\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShen\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCao\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Connexin-43 promotes survival of mesenchymal stem cells in ischaemic heart. Cell Biol Int 34\n\t\t\t\t\t415\n\t\t\t\t\t423 .\n\t\t\t'},{id:"B80",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeldrum\n\t\t\t\t\t\t\tK. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDinarello\n\t\t\t\t\t\t\tC. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeldrum\n\t\t\t\t\t\t\tD. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009 IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction. Proc Natl Acad Sci\n\t\t\t\t\t106\n\t\t\t\t\t17499\n\t\t\t\t\t17504 .\n\t\t\t'},{id:"B81",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhao\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQian\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKranias\n\t\t\t\t\t\t\tE. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFan\n\t\t\t\t\t\t\tG. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009 Hsp20-engineered mesenchymal stem cells are resistant to oxidative stress via enhanced activation of Akt and increased secretion of growth factors. Stem Cells\n\t\t\t\t\t12\n\t\t\t\t\t3021\n\t\t\t\t\t3031 .\n\t\t\t'},{id:"B82",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWoo\n\t\t\t\t\t\t\tY. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPanlilio\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCheng\n\t\t\t\t\t\t\tR. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiao\n\t\t\t\t\t\t\tG. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAtluri\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHsu\n\t\t\t\t\t\t\tV. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCohen\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChaudry\n\t\t\t\t\t\t\tH. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006 Therapeutic delivery of cyclin A2 induces myocardial regeneration and enhances cardiac function in ischemic heart failure. Circulation 114(Supl.1):I206\n\t\t\t\t\t213 .\n\t\t\t'},{id:"B83",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHo\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYet\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011 A central role of heme oxygenase-1 in cardiovascular protection. Antioxidants & Redox signalling ;epub ahead of print.\n\t\t\t'},{id:"B84",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoshimitsu\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHiguchi\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDawood\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRasaiah\n\t\t\t\t\t\t\tV. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAyach\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMedin\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006 Correction of cardiac abnormalities in fabry mice by direct intraventricular injection of a recombinant lentiviral vector that engineers expression of alpha-galactosidase A. Circ J\n\t\t\t\t\t70\n\t\t\t\t\t1503\n\t\t\t\t\t1508 .\n\t\t\t'},{id:"B85",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZancarelli\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSoltys\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRengo\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRabinowitz\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Analysis of AAV serotypes 1-9 mediated expression and tropism in mice after systemic injection. Mol Ther\n\t\t\t\t\t16\n\t\t\t\t\t1073\n\t\t\t\t\t1080 .\n\t\t\t'},{id:"B86",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZentilin\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPuligadda\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLionetti\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZacchigna\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCollesi\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPattarini\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRuozi\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCamporesi\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSinagra\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPepe\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRecchia\n\t\t\t\t\t\t\tF. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGiacca\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction. FASEB J\n\t\t\t\t\t24\n\t\t\t\t\t1467\n\t\t\t\t\t1478 .\n\t\t\t'},{id:"B87",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tJ. C. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWoo\n\t\t\t\t\t\t\tY. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSwain\n\t\t\t\t\t\t\tJ. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSweeney\n\t\t\t\t\t\t\tH. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999 Efficient transmural cardiac gene transfer by intrapericardial injection in neonatal mice. 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P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuyton\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVinten-Jonasen\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003 Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579\n\t\t\t\t\t88 .\n\t\t\t'},{id:"B90",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhao\n\t\t\t\t\t\t\tX. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHu\n\t\t\t\t\t\t\tS. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tli\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMou\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChan\n\t\t\t\t\t\t\tC. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJin\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSun\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tZ. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006 rAAV-mediated angiogenin gene transfer induces angiogenesis and modifies left ventricular remodeling in rats with myocardial infarction. J Mol Med\n\t\t\t\t\t84\n\t\t\t\t\t1033\n\t\t\t\t\t1046 .\n\t\t\t'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Guro Valen",address:"",affiliation:'
University of OsloDepartment of Physiology/Center for Heart Failure Research, Norway
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1. Introduction
Graft-versus-host disease (GVHD) is a debilitating complication that can determine the prognosis of allogeneic hematopoietic stem cell transplantation (HSCT) and subject 40–60% of HSCT recipients to a risk of death and disability [1]. GVHD is composed of acute GVHD (aGVHD) and chronic GVHD (cGVHD). For the classification of the 2 types of GVHD, the classifier should be clinical manifestations instead of time after HSCT [2]. However, in many cases, aGVHD appears within 100 days after HSCT and causes severe inflammation mostly in the skin, gastrointestinal tract, and liver [3]. cGVHD generally occurs systemically 6 months or later after HSCT, and its symptoms are similar to those of autoimmune diseases [4]. Complex interactions between donor and host immune cells are implicated in the pathogenesis of GVHD. It is thought that aGVHD is induced primarily by donor T cells’ cytotoxic responses against host tissues through recognition of host polymorphic histocompatibility antigens [5]. On the other hand, the mechanisms of cGVHD are more complicated and still poorly understood [6]. Although the use of corticosteroids alone or in combination with immunosuppressive agents is the recommended first-line strategy for the treatment of GVHD, its efficacy is not satisfactory [3, 7]. The prevalence of allogeneic HSCT for the treatment of hematologic diseases has increased the need for the development of efficacious second-line therapies which can mitigate symptoms of GVHD without compromising a graft-versus-leukemia effect, where donor T cells eliminate host leukemia cells. To date, various signaling pathways and pathogenic events in the context of GVHD have been intensively investigated. As a result, several FDA-approved drugs for GVHD have recently emerged. This chapter concisely summarises therapeutic targets and newly emerging drugs for the 2 forms of GVHD with the goal to facilitate the development of novel GVHD treatments for human use.
2. Clinical manifestations of GVHD
aGVHD can occur after the engraftment of donor-derived cells in the transplant recipient [8]. Symptoms of aGVHD can develop within weeks after the transplantation [9]. It has been believed that aGVHD can primarily affect the skin, gastrointestinal (GI) tract, and/or liver [10]. HSCT recipients can manifest rash, increased bilirubin, diarrhea, and vomiting [11]. Most recently, mounting evidence suggests that other organs such as the central nervous system, lungs, ovaries and testis, thymus, bone marrow, and kidney can be susceptible to aGVHD [12].
Clinical manifestations of cGVHD are different from those of acute GVHD. The onset of chronic GVHD can be divided into the following 3 cases: (1) occurring when aGVHD is present, (2) emerging after a period of resolution from aGVHD, and (3) developing de novo [13]. Immune dysregulation and absence of functional tolerance are characteristic of cGVHD, and symptoms of cGVHD are reminiscent of those of autoimmune disorders [13]. Clinical presentations of cGVHD can be as follows: (i) rash, raised or discolored areas, skin thickening or tightening, (ii) dry eye or vision changes, (iii) dry mouth, white patches inside the mouth, (iv) diarrhea and weight loss, (v) shortness of breath due to lung disorders and (vi) abnormal liver function [14]. It was challenging for clinicians to reach an agreement on the diagnosis, the timing of treatment, and how to grade cGVHD [15]. In order to overcome these difficulties, the National Institute of Health (NIH) consensus created diagnostic criteria for cGVHD in 2005 and revised the criteria in 2014 [16, 17]. The authors considered the severity of involvement of the skin, mouth, eyes, gastrointestinal tract, liver, lungs, joint fascia, and genital tract in order to define manifestations of cGVHD in its target organs and establish a scoring system.
Corticosteroids are used with or without immunosuppressive drugs as the first-line therapy for aGVHD and cGVHD in clinical settings [3, 7, 18, 19]. However, approximately 50% of patients who receive steroid therapy will be resistant to it, although mechanisms of steroid resistance remain to be elucidated [3, 7, 18, 19]. In addition, corticosteroid therapies also cause various undesired effects such as diabetes, obesity, osteoporosis, hypertension, glaucoma, and liver damage [20]. Thus, medical settings are in need of effective treatments of steroid-refractory aGVHD and cGVHD [3, 7, 18, 19].
3. General GVHD biology
GVHD has a complex pathophysiology, which initially begins with damage to host tissues by chemotherapy and radiation therapy before allogeneic HSCT (Figure 1) [21]. Due to this, damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), and inflammatory cytokines are released [22]. These stimuli activate host dendritic cells (DCs), leading to the expression of major histocompatibility complex class I (MHC-I) and class II (MHC-II) on the host DCs [22]. The mature host DCs activate donor-derived T cells in the graft [22]. The activated donor T cells migrate to aGVHD-susceptible organs and promote the excessive production of pro-inflammatory cytokines such as interferon (IFN)-γ and interleukin (IL)-17 [23, 24]. It results in abnormal inflammation and tissue damage [23, 24]. While it is believed that donor-derived CD4+ and CD8+ T cells play a pivotal role in mediating aGVHD [25], several other types of immune cells are reportedly involved in the pathogenic process of aGVHD [26]. Neutrophils contribute to the development of intestinal aGVHD [27]. A previous report suggests that neutrophils in the ileum migrate to mesenteric lymph nodes, presenting antigens on their MHC-II and promoting T cell expansion [28]. Donor monocyte-derived macrophages with potent immunological functions are implicated in the pathophysiology of cutaneous aGVHD by secreting chemokines, stimulating T cells, and mediating direct cytotoxicity [29, 30]. In contrast, regulatory T cells (Tregs) are thought to serve a suppressive role in aGVHD without significantly reducing the graft-versus-leukemia (GVL) effect [31, 32]. Recent reports suggest that donor-derived natural killer (NK) cells can have an inhibitory effect in aGVHD by promoting the depletion of allo-reactive T cells while showing the GVL effect [33]. A recent study indicates that the occurrence and severity of aGVHD could be associated with the disordered reconstitution of CD56high NK cells [34].
Figure 1.
The overview of aGVHD pathogenesis. The preconditioning regimen causes tissue damage. It generates DAMPs, PAMPs and proinflammatory cytokines such as TNFα, IL-1β and IL-6, which activates host APCs. The activated APCs present antigens to donor T cells, and the activated T cells infiltrate aGVHD target organs and produce an excessive amount of IFNγ and IL-17, leading to abnormal inflammation and tissue damage. This figure is created with BioRender.
While mechanisms of cGVHD are still incompletely understood, recent evidence suggests that there are several observations characteristic of cGVHD (Figure 2) [35]. The thymus is damaged due to the conditioning regimen and/or the prior occurrence of aGVHD, leading to impaired negative selection of alloreactive CD4+ T cells [36]. Alloreactive T cells are activated by antigen-presenting cells (APCs), resulting in their expansion and polarization toward type 1, type 2, and type 17 helper T (Th1, Th2, and Th17) cells [35]. These immune deviations lead to the production of proinflammatory and profibrotic inflammatory cytokines such as IFNγ, IL-6, IL-17, IL-4, and transforming growth factor β (TGFβ), which skew macrophages and fibroblasts towards proinflammatory and/or profibrotic phenotypes [35]. Consequently, inflammation and fibrosis are induced in cGVHD target organs [37]. The damaged thymic epithelial cells (required for the generation of Tregs as well as the negative selection) also cause a decrease in the number of Tregs [38]. Furthermore, the dysregulation of B cells causes autoreactive B cells to arise and produce autoreactive antibodies [39]. The emergence and activation of autoreactive B cells presumably stem from B cell exhaustion induced by aberrant levels of B cell-activating factor (BAFF) in the lymphoid microenvironment [40, 41].
Figure 2.
Overview of cGVHD pathogenesis. The thymus is damaged due to the preconditioning regimen and/or aGVHD. Due to the damage, the negative selection of alloreactive T cell is impaired. Alloreactive T cells are polarised into Th1, Th2 or Th17 cells. Th1 cells produce IFNγ, which drives macrophages to an M1-like phenotype to promote inflammation. IL-4, IL-10 and TGFβ produced by Th2 cells facilitate macrophage differentiation into an M2-like phenotype. Activation and proliferation of tissue fibroblasts are induced by (i) TGFβ from Th2 cells, (ii) PDGFα and TGFβ from M2-like macrophages and (iii) IL-6 and IL-17 from Th17 cells, leading to collagen production and fibrosis. B cells are activated by IL-6 and IL-17 from Th17 cells, and the alloreactivity of B cells is presumably induced by an excessive amount of BAFF. As a result of the above events, systemic inflammation and fibrosis are induced, and autoimmune-like manifestations are observed. This figure is created with BioRender.
4. Therapeutic targets and strategies for GVHD
4.1 TCR and BCR signaling
When the T cell receptor (TCR) interacts with an MHC-antigenic peptide complex, it induces molecular and cellular changes in T cells [42]. A wide range of signal transduction pathways in T cells is stimulated due to this interaction, leading to the activation of a variety of genes [43]. Effector enzymes such as kinases, phosphatases, and phospholipases are involved in the TCR signaling pathways, which are integrated by non-enzymatic adaptor proteins acting as a scaffold for interactions between proteins [42]. These intracellular signaling pathways can determine the features of immunity mediated by T cells [44].
The B cell receptor (BCR) complexes on inactivated B cells act as self-inhibiting oligomers [45]. The BCR signaling pathways are initiated, when BCR is bound to an antigen and induces actin-mediated nanoscale recombination of receptor clusters [46]. Due to this event, the BCR oligomers are opened and the ITAM domains are revealed, resulting in the transduction of intracellular signals which are crucial for B cell development, activation, proliferation, differentiation, and antibody production in health and disease [47].
In 2017, FDA approved ibrutinib, which targets B cells and T cells, for the treatment of cGVHD. Ibrutinib was the first FDA-approved drug for steroid-refractory cGVHD, and it was a significant milestone for GVHD research [48]. Ibrutinib is reported to modulate the functions of B cells and T cells by potently inhibiting Bruton’s Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) [49], which are involved in the B cell signaling and T cell signaling pathways, respectively. Treatment of cGVHD-affected recipients with ibrutinib resulted in decreased serum-autoantibodies and B-cell proliferation [50]. Data from the clinical trials show that symptoms of cGVHD improved in 67% of patients treated with ibrutinib [48].
4.2 Purinergic signaling
The Purinergic signaling pathways play a crucial role in a range of physiological systems including the immune system. In the purinergic signaling pathways, extracellular purine nucleosides and nucleotides such as adenosine and adenosine triphosphate (ATP) are used as signaling molecules that mediate the communication between cells through the activation of purinergic receptors [51]. There are four types of P1 (adenosine) receptors (A1, A2A, A2B, and A3). P2 receptors are subdivided into P2X and P2Y [52]. P2X receptors have seven subtypes (P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7), and P2Y receptors have 8 subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) [52].
As demonstrated by several studies using mouse models of aGVHD, extracellular ATP is augmented in aGVHD-affected mice, and purinergic signaling is implicated in the pathogenic process of aGVHD (Figure 3) [53]. The conditioning regimens prior to allo-HSCT can induce tissue damage, leading to the release of DAMP molecules including ATP, which activates purinergic signaling [53]. The involvement of extracellular ATP is evidenced by the fact that the injection of the soluble ATP diphosphohydrolase (ATPDase) can reduce inflammation in aGVHD target organs and the serum level of IFNγ [53, 54].
Figure 3.
Link between GVHD and the therapeutically targetable purinergic signaling pathways. In aGVHD, ATP is produced due to tissue damage. Host APCs and donor T cells can be activated by the P2X7 receptor, which results in the progression of aGVHD. The activation of donor Tregs can also be induced by the ATP-activated P2X7 receptor, which leads to the reduction of Treg survival and the progression of aGVHD. CD39 and CD73 on donor Tregs can degrade ATP to adenosine. Adenosine can activate the A2A receptor on donor T cells, which culminates in the decrease in the number of CD4+ and CD8+ T cells and the reduction of aGVHD. In cGVHD, ATP is also released because of tissue damage and may promote fibroblast-to-myofibroblast transition through the ATP-activated P2X7 receptor, leading to the augmented collagen production and the progression of tissue fibrosis. In contrast, the ATP-activated P2Y14 receiptor may prevent cellular senescence in macrophages and mitigate cGVHD. This figure is created with BioRender.
Evidence suggests that; (i) P2X7 is a crucial P2X receptor in the development of aGVHD after the release of extracellular ATP, (ii) the expression of the P2X7 receptor is elevated in PBMCs in aGVHD patients, (iii) the liver, spleen, skin, and thymus in aGVHD-affected mice show the increased expression of the P2X7 receptor, (iv) the ATP-induced the activation of the P2X7 receptor on host APCs can facilitate the stimulation, proliferation, and survival of donor T cells during aGVHD and (v) the P2X7 activation on host APCs may be associated with the expression of microRNA mir-155 [53, 55, 56, 57].
While the host P2X7 receptor is shown to play an integral role in the development of aGVHD, the donor P2X7 receptor is also a contributor to this disease. Evidence suggests that (i) the activation and proliferation of donor CD4+ T cells and (ii) the metabolic fitness of donor CD8+ T cells are also enhanced by the activated donor P2X7 receptor [58, 59]. In addition, the activation of P2X7 on donor Tregs can reduce their suppressive ability and stability of Tregs, promoting their conversion to Th17 cells [60].
Inhibition of the P2X7 receptor is reported to mitigate aGVHD in conventional and humanised mouse models of aGVHD. Treatment of allogeneic HSCT recipient mice with the P2X7 inhibitor pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) can increase the survival rate and the number of Tregs, and reduce the serum level of IFNγ and histological aGVHD [53, 54]. Administration of the P2X7 inhibitor brilliant blue G (BBG) to allogeneic HSCT recipient mice can also prevent weight loss and reduce inflammation in the liver and the production of inflammatory cytokines [56]. Furthermore, a crystal structure of the P2X7 receptor in complex with the inhibitor AZ10606120 has been reported (PDB: 5U1W) [61], and this structural information could be useful for the design and synthesis of novel P2X7 inhibitors which can be used in clinical settings.
The P2Y2 receptor is also reported to contribute to the pathogenesis of aGVHD [22, 57]. Evidence indicates that the number of cells expressing the P2Y2 receptor is increased in the intestinal tract in aGVHD-affected mice and that the increased P2Y2 expression enhances the severity of intestinal aGVHD [62]. Of note, knock-out allogeneic HSCT recipient mice of the P2Y2 receptor show an increased survival rate and decreased cytokine levels [62]. However, in the case where the P2Y2 receptor in donor cells is knocked out, no such improvement is observed [62]. In contrast, literature precedent suggests that the activation of the P2Y2 receptor can promote the migration of Tregs to sites of inflammation and thereby mitigate aGVHD [63]. Due to the dual functions of the P2Y2 receptor, targeting the P2Y2 receptor for the treatment has been challenging and there have been no reports about systemic injection of P2Y2 inhibitors/activators for the treatment of aGVHD [64].
While ATP is released in damaged tissues in allogeneic HSCT recipients and promotes inflammation, it is also degraded to adenosine by CD39 and CD73 [53]. In particular, a murine study indicates that CD39 and CD73 are highly expressed on CD150high Tregs [65]. As shown by a study using a mouse model of aGVHD, inhibition of CD39 and CD73 with adenosine 5′-(α,β-methylene)diphosphate (APCP) leads to the increase in the number of splenic CD4+ and CD8+ T cells, the serum levels of IFNγ and IL-6, and the mortality rate [66]. These data suggest that CD39 and CD73 play an alleviatory role in aGVHD. Evidence demonstrates that the production of adenosine by CD39 and CD73 results in the activation of the adenosine A2A receptor [66, 67, 68]. The activated A2A receptor can induce the expansion of donor Tregs and thereby mitigate aGVHD-induced inflammation [66, 67, 68]. The blockade of A2A with the antagonist SCH58261 exacerbates aGVHD by elevating the levels of TNFα, IFNγ, and IL-6 and the number of CD4+ and CD8+ T cells in sera [66]. In agreement with this report, the A2A agonist ATL-146e reduced weight loss and mortality in aGVHD-affected mice by (i) increasing serum IL-10 and reducing serum IFN-γ and IL-6, (ii) precluding the activation of splenic CD4+ and CD8+ T cells, and the infiltration of T cells into GVHD target organs [67]. Other A2A agonists, ATL-370 and ATL-1223, are reported to exert similar therapeutic effects on aGVHD [68]. Moreover, a crystal structure of the A2A receptor in complex with the activator ZM241385 has been reported (PDB: 5WF5) [69], and this structural information could facilitate the creation of novel A2A activators which can enter the clinic.
Although there are few to no reports about a link between purinergic signaling and cGVHD pathogenesis, activation of the P2X7 receptor is reported to promote fibroblast-to-myofibroblast transformation and contribute to the development of fibrosis [70]. The activation of the P2X7 receptor enhances Ca2+ influx and skews fibroblasts towards a fibrogenic phenotype, leading to augmented collagen production [70]. Considering fibrosis is a significant hallmark of cGVHD, the investigation into a correlation between purinergic signaling and fibroblast activity in cGVHD could open up a new window for the elucidation of mechanisms of cGVHD and the development of novel drugs for cGVHD (Figure 3). Furthermore, stress-induced cellular senescence in immune cells is reported to play a detrimental role in the pathogenesis of ocular cGVHD [71, 72], and a murine study indicates that the P2Y14 receptor modulates stress-induced cellular senescence in hematopoietic stem/progenitor cells [73]. Given these findings, the P2Y14 receptor may be a regulator of stress-induced cellular senescence in cGVHD, and development of agonists of the P2Y14 receptor could benefit cGVHD patients.
4.3 JAK/STAT signaling
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways are regarded as a central communication junction for the immune system [74]. In the JAK/STAT signaling pathways, the cytoplasmatic kinase JAKs interact with the transcription factor STATs, and more than 50 cytokines and growth factors are involved in the JAK/STAT signaling pathways [75]. Mammals have 4 JAKs (JAK1, JAK2, JAK3, JAK4) and 7 STATs (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6) [76], and the dysregulated JAK/STAT signaling pathways contribute to a variety of human diseases, which makes this signaling a promising drug target [77].
In the early phase of aGVHD, tissue damage due to the preconditioning regimen and the disease results in the release of DAMPs, leading to the increased expression of MHC on APCs at the infusion of donor cells [78]. Donor T cells are activated via direct or indirect allorecognition, and the activated donor T cells produce IFNγ to initiate the JAK/STAT signaling pathways through IFNγ receptors [78]. The resultant increase in the expression of the chemokine receptor CXCR3 on T cells enhances their migration to aGVHD target organs, which promotes tissue damage [79].
While clinical manifestations of cGVHD are different from those of aGVHD, they have similarities in some aspects of the pathogenic processes [80]. The JAK/STAT signaling pathways in the context of cGVHD have been intensively investigated [81]. Tregs play a crucial role in the reduction of cGVHD, and JAK1/JAK2 signaling pathways are thought to negatively regulate the development and proliferation of Tregs, as indicated by the fact that JAK2 inhibition can promote Treg proliferation [82, 83]. Tissue fibrosis is highly problematic in cGVHD, and M2-like macrophages producing TGF-β are presumably a key player [84]. IL-10 skews macrophages towards an M2-like phenotype through the IL-10 receptor-JAK1/STAT3 pathway [85]. Given these reports, it would be intriguing to investigate an association between macrophages and the JAK/STAT signaling pathways in the development of cGVHD-induced fibrosis.
Many researchers have focused on the development of inhibitors targeting JAK/STAT signaling pathways for the treatment of aGVHD and cGVHD [81]. As demonstrated by several preclinical data, inhibition of the JAK/STAT pathways can mitigate GVHD without affecting the GVL effect [81] Most recently, the JAK1/JAK2 inhibitor ruxolitinib has been approved by FDA for aGVHD and cGVHD. In 2019, FDA approved ruxolitinib to treat steroid-refractory aGVHD patients 12 years or older [86]. The clinical trials show that the day-28 overall response rate (ORR) was 100% for Grade 2 aGVHD, 40.7% for Grade 3 aGVHD, and 44.4% for Grade 4 aGVHD [86]. In 2021, FDA approval was also granted to ruxolitinib for the therapy of steroid-resistant cGVHD patients 12 years or older [87]. The clinical trial data demonstrate that the ORR was 70%, and the median durations of response, which were calculated from first response to progression, death, or new systemic therapies for cGVHD, were 4.2 months [87]. A crystal structure of JAK2 in complex with ruxolitinib is provided in the PDB database (PDB: 6VGL) [88], and this structural information could be useful for the design of more potent and selective JAK1/JAK2 inhibitors. Another promising JAK1 inhibitor is itacitinib [89]. Data from a phase 1 clinical trial of itacitinib shows that 70.6% of steroid-refractory cGVHD patients were treated in a satisfactory manner [90]. Furthermore, two clinical trials of itacitinib for cGVHD have recently commenced (ClinicalTrials.gov identifier: NCT04200365, NCT03584516). It is of great medical significance that novel drugs targeting the JAK/STAT signaling will continue to be developed for the treatment of aGVHD and cGVHD.
4.4 NF-κB signaling
The transcription factor nuclear factor kappa B (NF-κB) controls the expression of various genes important for the induction of inflammatory responses in innate and adaptive immune cells [91]. NF-κB is a family of heterodimers or homodimers generated from different combinations of the following 5 proteins: p65/RelA, RelB, c-Rel, p105/p50 (NF-κB1), and p100/p52 (NF-κB2) [92]. Among them, the p50/p65 complex is thought to be the most abundant form of NF-κB dimer [93]. When NF-κB is inactive, it is retained in the cytoplasm by the IκB family of inhibitors [94, 95]. In response to a wide range of stimuli such as the proinflammatory cytokines IL-1 and TNF-α, IκB kinase (IKK) is activated to phosphorylate the 2 serine residues of IκBα [96]. The phosphorylation causes the 26S proteasome to induce the ubiquitination and degradation of IKβ. Subsequently, NF-κB is translocated into the nucleus and triggers gene transcription, leading to the production of proteins necessary for immune responses [97]. Thus, NF-κB is regarded as a therapeutic target for the treatment of various inflammatory diseases.
The NF-κB signaling pathways have captured increasing attention from GVHD researchers. It has been reported that the activation of RelB in APCs contributes to the expansion of donor Th1 cells and subsequent alloreactivity, which leads to the development of aGVHD [98]. The NF-kB signaling pathways can be survival and proliferation signals and contribute to B-cell alloantibody deposition and germinal center formation, which play a critical role in the pathogenic process of cGVHD [99, 100].
Bortezomib is an FDA-approved drug for the treatment of multiple myeloma and is known to be an indirect inhibitor of NF-κB [101]. A murine study suggests that aGVHD can be prevented by treatment with bortezomib early after allogeneic HSCT [102, 103]. Bortezomib is undergoing clinical trials for aGVHD (BMT CTN 1203), and the phase1/2 study shows that bortezomib can be used in combination with tacrolimus and methotrexate in a tolerable immunosuppressive regimen after allogeneic HSCT [104]. Bortezomib can also be effective for the treatment of cGVHD. NF-κB inhibition with Bortezomib is suggested to cause apoptosis of germinal center B cells during reconstitution, leading to the decrease in donor-derived B cell numbers and BAFF expression [103]. With these promising data, clinical trials of bortezomib for the treatment of steroid-refractory cGVHD are in progress (NCT01158105). At present, there are no NF-κB inhibitors approved by FDA for aGVHD or cGVHD. Generally, direct inhibitors are superior to indirect ones in terms of selectivity. Thus, novel direct NF-κB inhibitors with high selectivity are greatly anticipated for the treatment of GVHD.
4.5 Hedgehog signaling
The Hedgehog signaling pathways are involved in the regulation of cell proliferation, survival, and differentiation [105], and its aberrant activation contributes to detrimental events such as the self-renewal and metastasis of cancer stem cells [106]. In the absence of Hedgehog ligand (Hh), the activation of Smoothened (SMO) is inhibited by Patched (PTCH) [107]. Subsequently, the activity of glioma-associated oncogene homolog (Gli) is suppressed by a protein complex mainly composed of a suppressor of fused (SUFU), which phosphorylates Gli and prevents it from entering the nucleus. In the presence of Hh, the binding of Hh to PTCH precludes the SMO inhibition mediated by PTCH [107]. Activated SMO prevents phosphorylation of Gli mediated by the SUFU complex, leading to the migration of Gli to the nucleus and the induction of downstream target gene expression [107].
Fibrosis is a highly problematic feature of cGVHD, and a profibrotic activity of Hedgehog signaling in patients and mouse models of cGVHD has been reported [108]. Overexpression of Hh, which is an inducer of the Hedgehog signaling pathways, is observed in human and murine sclerodermatous cGVHD [108]. The downstream processes of the Hedgehog signaling pathway cause overexpression of Gli-1 and Gli-2, particularly in fibroblasts [109]. The abnormal expression of Gli-1 and Gli-2 may result in the overproduction of collagen and the resultant pathologic fibrosis in cGVHD target organs [109]. Furthermore, the Hedgehog signaling is suggested to contribute to the increase of profibrotic M2-like macrophages in the cGVHD-affected skin [109].
There are several inhibitors of the Hedgehog pathways. Among others, sonidegib, vismodegib, and glasdegib are SMO inhibitors approved by FDA for the treatment of basal cell carcinoma [110]. These 3 SMO inhibitors are currently undergoing clinical trials for cGVHD therapy (NCT02086513, NCT02337517, NCT04111497). According to a report of the Phase-1 trial of sonidegib, where 17 steroid-refractory cGVHD patients participated, protein expression of hedgehog signaling pathway molecules was decreased by treatment with sonidegib as judged by immunohistochemical evaluation of the skin [111]. With respect to the creation of novel SMO inhibitors for the treatment of GVHD, Lacroix et al. found a potential SMO inhibitor by performing structure-based virtual screening of 3.2 million available, lead-like molecules against Smoothened and subsequent biological validations of the top-ranked compounds [112]. This information could benefit the design and synthesis of more potent and selective inhibitors of SMO.
4.6 Endoplasmic reticulum stress
While elucidation of mechanisms of cGVHD is still elusive, chronic inflammation is characteristic of cGVHD [113]. Senescent macrophages contribute to ocular cGVHD in mice, and gray eyebrows, skin wrinkles and conjunctival cancer are observed in human cGVHD [71, 114]. These findings suggest that ageing in donor- and recipient-derived cells is induced in cGVHD [71]. Evidence suggests that chronic inflammation and age-related diseases are associated with the elevation of endoplasmic reticulum (ER) stress [115, 116]. Mukai et al found that ER stress was increased in organs affected by cGVHD in mice [117]. Treatment of cGVHD-affected mice with the known ER stress reducer 4-phenylburyric acid (PBA) resulted in mitigation of systemic inflammation and fibrosis induced by cGVHD [117]. Of note, PBA is approved by FDA for the treatment of urea cycle disorders, and its safety was proven [118]. Investigation at the cellular level indicates that ER stress contributes to fibrosis as well as inflammation induced by cGVHD. Elevated ER stress caused (i) the dysregulation of lacrimal-gland-derived fibroblasts and (ii) abnormal production of MCP-1/CCL2, IL-6, and connective tissue growth factor (CTGF) [117]. Suppression of ER stress with PBA reduced their abnormal production of the inflammatory and fibrotic molecules [117]. In addition, ER stress induced by cGVHD skewed splenic macrophages towards an M2-like phenotype, and treatment of them with PBA promoted their differentiation into an M1-like phenotype [117]. Several reports also indicate that the augmentation of M2-like macrophages is implicated in the progression of cGVHD [84, 119, 120]. M2-like macrophages are thought to contribute to the pathogenesis of fibrosis-associated diseases [121], and it seems to be the case with cGVHD. As these analyses were performed in a bulk population, further investigation will be needed. Macrophages and fibroblasts are known to be heterogeneous populations [122, 123, 124, 125]. In particular, mounting evidence suggests that macrophage heterogeneity is multidimensional and more complex than M1/M2 classification [126]. Hence, single-cell analyses could greatly facilitate the understanding of a correlation between ER stress and macrophages/fibroblasts in the development of cGVHD and make ER stress a more compelling therapeutic target for cGVHD therapy.
4.7 Aberrant immune cell infiltration
While aGVHD and cGVHD show different clinical manifestations, one of their common features is abnormal immune cell infiltration, which results in organ damage and severe inflammation and fibrosis. Mukai et al devised a novel therapeutic strategy for both types of GVHD by targeting vascular adhesion protein-1 (VAP-1) [127], which is known to be overexpressed in inflamed organs [128]. VAP-1 is an endothelial surface glycoprotein assisting leucocyte migration from the bloodstream to tissues and possesses the following 2 functional domains: a distal adhesion domain and a catalytic amine oxidase domain [129]. For infiltration into tissues, the amino group in leukocytes undergoes a nucleophilic attack on the carbonyl group in VAP-1 [129]. The subsequent catalytic conversion of the primary amine to the corresponding aldehyde allows immune cells to squeeze into tissues through blood vessels [129, 130]. Pursuant to their study with the use of a mouse model where aGVHD shifts to cGVHD [127], (i) the protein expression of VAP-1 is increased in organs with GVHD, where the number of inflammatory cells is accordingly augmented, (ii) blockade of VAP-1 with a novel inhibitor reduced the number of tissue-infiltrating leukocytes and thereby mitigated GVHD manifestations such as inflammation and fibrosis and (iii) the VAP-1 inhibition caused few to no severe adverse effects. Collectively, inhibition of VAP-1 could be an effective all-in-one approach for the treatment of aGVHD and cGVHD.
4.8 NOTCH signaling
The Notch signaling pathways are cell-to-cell communication induced by interactions between Notch receptors (NOTCH1, NOTCH2, NOTCH3, and NOTCH4) and NOTCH ligands (Jagged1 (JAG1), JAG2, Delta-like 1 (DLL1), DLL3 and DLL4) [131]. Due to these intercellular interactions, the NOTCH receptor is proteolytically activated by an ADAM family metalloprotease and subsequently by the γ-secretase complex [132]. The sequential cleavages lead to the release of the intracellular NOTCH domain (NICD), which is a transcriptionally active fragment [133]. NICD migrates to the nucleus and binds to the DNA binding CSL/RBP-Jk factor, forming a transcriptional activation complex with a mastermind-like (MAML) family coactivator [133]. This final complex triggers the transcription of target genes which are important for biological processes such as proliferation, differentiation, and survival [134].
A correlation between the Notch signaling pathways and alloimmune responses has gained interest from GVHD researchers. Studies using animal models of aGVHD suggest that; (i) the Notch signaling promotes activation, differentiation, and alloreactivity of T cells [135] and (ii) dendritic cells with high DLL4 expression show an increase in the production of IFN-γ and IL-17 [136]. The Notch signaling is also implicated in the pathogenic process of cGVHD. A murine study shows that NOTCH1 and NOTCH2 as well as DLL1 and DLL4 serve significant functions in regulating proinflammatory cytokine production by T cells [137]. Investigation using in-vitro human B-cell assay systems demonstrates that abnormal activation of NOTCH2 is correlated with hyperresponsiveness of BCR on B cells from cGVHD patients [138].
GVHD treatments by targeting the Notch signaling pathway have been reported. A series of experiments using a mouse model of aGVHD reveals; (i) inhibitors of γ-secretase block proteolytic activation of all the NOTCH receptors, but has severe toxicity in the gut epithelium, (ii) NOTCH1 inhibition using an antibody mitigates GVHD but causes serious toxicity and (iii) treatment with a combination of anti-DLL1 and anti-DLL4 reduces aGVHD without debilitating adverse effects while maintaining a GVL effect of donor T cells [139]. An anti-DLL1 antibody is also effective for the treatment of murine cGVHD in combination with an anti-DLL4 antibody [137]. Treatment with all-trans-retinoic acid (ATRA) prevents NOTCH2-induced BCR hyperresponsiveness, which plays a detrimental role in cGVHD pathogenesis [137]. It appears that NOTCH2 and DLL1/4 are promising drug targets for the treatment of the 2 types of GVHD. Therefore, it is highly anticipated that novel, selective inhibitors of NOTCH2 and DLL1/4 will be developed for use in human GVHD.
4.9 Rho/ROCK signaling
Rho-associated coiled-coil-containing protein kinases (ROCKs) are serine-threonine-specific protein kinases, and mammals have ROCK1 and ROCK2 [140]. ROCKs are downstream effector proteins of GTPase Rho, and abnormal activation of the Rho/ROCK pathways contributes to the development of various diseases [140]. In particular, ROCK2 is known to regulate (i) the balance of Th17 cells and Tregs and (ii) profibrotic pathways [141]. ROCK2 activation increases Th17 cell-specific transcription factors by promoting STAT3 phosphorylation [142]. In addition, when ROCK2 is activated by profibrotic mediators such as tumor growth factor-β (TGF-β), it causes myocardin-related transcription factors to activate profibrotic genes in fibroblasts [143, 144]. This profibrotic gene activation induces fibroblast-to-myofibroblast differentiation and the resultant increase in collagen production [143, 144].
A study using a cGVHD mouse model shows that treatment with belumosudil, which is a selective ROCK2 inhibitor, can substantially reduce cGVHD-induced fibrosis in the lung [145]. In 2021, belumosudil was approved by FDA for the treatment of cGVHD, and the clinical trial data show that the overall response rate was 75% (6% complete response and 69% partial response) [146].
ROCK1 is also thought to be involved in the development of fibrosis, and pan-ROCK inhibitors targeting ROCK1/2 are thereby expected to show better treatment outcomes for cGVHD [147]. Several pan-ROCK inhibitors have been granted approval for human use [148, 149, 150, 151] In particular, netarsudil has been approved by FDA for the treatment of glaucoma [151]. However, due to a lack of overall kinome selectivity of the reported dual ROCK1/2 inhibitors, there is still scope for improvement in pan-ROCK inhibitors [152]. Hu et al. has recently reported the synthesis and in-vitro evaluation of a novel series of 5H-chromeno[3,4-c]pyridine, 6H-isochromeno[3,4-c]pyridine, and 6H-isochromeno[4,3-d]pyrimidine derivatives as dual ROCK1/2 inhibitors [152]. Their data show that some of the novel pan-ROCK inhibitors display potent inhibitory activity against ROCK1/2 and possess excellent kinome selectivity [152]. They also provided a crystal structure of ROCK2 in complex with one of the novel dual ROCK1/2 inhibitors (PDB ID: 7JNT). This structural information can be useful in the structure-based design of other new pan-ROCK inhibitors.
5. Conclusion
While recent decades have seen significant technological and medical advances, aGVHD and cGVHD are still a major hurdle to successful allogeneic HSCT in clinical settings. Systemic corticosteroid therapy, with or without immunosuppressive agents, is the first-line treatment for GVHD, although it can cause severe adverse effects and approximately 50% of GVHD patients develop steroid-resistant GVHD. Thus, sophisticated treatments of steroid-refractory aGVHD and cGVHD are highly anticipated by medical settings. A great deal of effort has been invested in the elucidation of mechanisms of GVHD and development of safe and efficacious drugs for GVHD. Recently, several drugs have been approved by FDA for the treatment of steroid-refractory aGVHD and cGVHD. Despite this progress, there is still a need to create novel drugs with better efficacy for GVHD therapy. This chapter focused on druggable targets for the treatment of GVHD with an aim to stimulate various GVHD researchers (from medicinal chemists to biologists) to create novel drugs which can enter the clinic. While several signaling pathways have been intensively studied in the context of GVHD, there are underexplored signaling pathways. In particular, the purinergic signaling pathway is one of the understudied signaling pathways in GVHD. The P2X7, A2A, and P2Y14 receptors seem to be compelling drug targets for the treatment of GVHD, and clinical settings could benefit from safe and efficacious (i) inhibitors of the P2X7 receptor and (ii) activators of the A2A and/or P2Y14 receptors. However, the development of new drugs is a costly and time-consuming process. To overcome this setback, the use of AL/ML has captured great interest from many researchers and has been expected to substantially reduce the cost and time of drug development. A combination of AL/ML and molecular design could greatly facilitate the development of novel, effective, safe, and affordable drugs for the treatment of GVHD.
\n',keywords:"inflammation, fibrosis, therapeutic targets, drug development",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81580.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81580.xml",downloadPdfUrl:"/chapter/pdf-download/81580",previewPdfUrl:"/chapter/pdf-preview/81580",totalDownloads:26,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 19th 2022",dateReviewed:"March 10th 2022",datePrePublished:"April 29th 2022",datePublished:null,dateFinished:"April 29th 2022",readingETA:"0",abstract:"Graft-versus-host disease (GVHD) is a disabling complication after allogeneic hematopoietic stem cell transplantation (HSCT) and negatively impacts patients’ quality of life. GVHD is classified into 2 forms according to clinical manifestations. Acute GVHD (aGVHD) typically affects the skin, gastrointestinal tract, and liver, whereas chronic GVHD occurs systemically and shows diverse manifestations similar to autoimmune diseases such as eosinophilic fasciitis, scleroderma-like skin disease. GVHD is induced by complicated pathological crosstalk between immune cells of the host and donor and involves various signaling pathways such as purinergic signaling. Although the past several decades have seen significant progress in the understanding of mechanisms of GVHD and several drugs have been approved by FDA for the prevention and treatment of GVHD, there is still vast scope for improvement in the therapy for GVHD. Thus, new drugs for GVHD will need to be developed. Towards this goal, this chapter succinctly summarises the pathogenic process of GVHD and emerging GVHD treatments in order to provide some insights into the mechanisms of GVHD and facilitate the development of novel drugs.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81580",risUrl:"/chapter/ris/81580",signatures:"Shin Mukai",book:{id:"10801",type:"book",title:"Purinergic System",subtitle:null,fullTitle:"Purinergic System",slug:null,publishedDate:null,bookSignature:"Dr. Margarete Dulce Bagatini",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-784-7",printIsbn:"978-1-80355-783-0",pdfIsbn:"978-1-80355-785-4",isAvailableForWebshopOrdering:!0,editors:[{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Clinical manifestations of GVHD",level:"1"},{id:"sec_3",title:"3. General GVHD biology",level:"1"},{id:"sec_4",title:"4. Therapeutic targets and strategies for GVHD",level:"1"},{id:"sec_4_2",title:"4.1 TCR and BCR signaling",level:"2"},{id:"sec_5_2",title:"4.2 Purinergic signaling",level:"2"},{id:"sec_6_2",title:"4.3 JAK/STAT signaling",level:"2"},{id:"sec_7_2",title:"4.4 NF-κB signaling",level:"2"},{id:"sec_8_2",title:"4.5 Hedgehog signaling",level:"2"},{id:"sec_9_2",title:"4.6 Endoplasmic reticulum stress",level:"2"},{id:"sec_10_2",title:"4.7 Aberrant immune cell infiltration",level:"2"},{id:"sec_11_2",title:"4.8 NOTCH signaling",level:"2"},{id:"sec_12_2",title:"4.9 Rho/ROCK signaling",level:"2"},{id:"sec_14",title:"5. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Jagasia M, Arora M, Flowers MED, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. 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We believe financial barriers should not prevent researchers from publishing their findings. With the need to make scientific research more publicly available and support the benefits of Open Access, more and more institutions and funders are dedicating resources to assist faculty members and researchers cover Open Access Publishing Fees (OAPFs). In addition, IntechOpen provides several further options presented below, all of which are available to researchers, and could secure the financing of your Open Access publication.
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Paying the OAPF
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At IntechOpen, the majority of OAPFs are paid by an Author’s institution or funding agency - Institutions (73%) vs. Authors (23%).
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The first step in obtaining funds for your Open Access publication begins with your institution or library. IntechOpen’s publishing standards align with most institutional funding programs. Our advice is to petition your institution for help in financing your Open Access publication.
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Please consult our Open Access Funding page to explore some of these funding opportunities and learn more about how you could finance your IntechOpen publication. Keep in mind that this list is not definitive, and while we are constantly updating and informing our Authors of new funding opportunities, we recommend that you always check with your institution first.
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IntechOpen Waivers in Action
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For Authors who are unable to obtain funding from their institution or research funding bodies and still need help in covering publication costs, IntechOpen offers the possibility of applying for a Waiver.
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Our mission is to support Authors in publishing their research and making an impact within the scientific community. Currently, 14% of Authors receive full waivers and 6% receive partial waivers.
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While providing support and advice to all our international Authors, waiver priority will be given to those Authors who reside in countries that are classified by the World Bank as low-income economies. In this way, we can help ensure that the scientific work being carried out can make an impact within the worldwide scientific community, no matter where an Author might live.
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The application process is open after your submitted manuscript has been accepted for publication. To apply, please fill out a Waiver Request Form and send it to your Author Service Manager. If you have an official letter from your university or institution showing that funds for your OA publication are unavailable, please attach that as well. The Waiver Request will normally be addressed within one week from the application date. All chapters that receive waivers or partial waivers will be designated as such online.
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Note: All data represented above was collected by IntechOpen from 2013 to 2017.
At IntechOpen, the majority of OAPFs are paid by an Author’s institution or funding agency - Institutions (73%) vs. Authors (23%).
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The first step in obtaining funds for your Open Access publication begins with your institution or library. IntechOpen’s publishing standards align with most institutional funding programs. Our advice is to petition your institution for help in financing your Open Access publication.
\n\n
However, as Open Access becomes a more commonly used publishing option for the dissemination of scientific and scholarly content, in addition to institutions, there are a growing number of funders who allow the use of grants for covering OA publication costs, or have established separate funds for the same purpose.
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Please consult our Open Access Funding page to explore some of these funding opportunities and learn more about how you could finance your IntechOpen publication. Keep in mind that this list is not definitive, and while we are constantly updating and informing our Authors of new funding opportunities, we recommend that you always check with your institution first.
\n\n
IntechOpen Waivers in Action
\n\n
For Authors who are unable to obtain funding from their institution or research funding bodies and still need help in covering publication costs, IntechOpen offers the possibility of applying for a Waiver.
\n\n
Our mission is to support Authors in publishing their research and making an impact within the scientific community. Currently, 14% of Authors receive full waivers and 6% receive partial waivers.
\n\n
While providing support and advice to all our international Authors, waiver priority will be given to those Authors who reside in countries that are classified by the World Bank as low-income economies. In this way, we can help ensure that the scientific work being carried out can make an impact within the worldwide scientific community, no matter where an Author might live.
\n\n
How to Apply for a Waiver
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The application process is open after your submitted manuscript has been accepted for publication. To apply, please fill out a Waiver Request Form and send it to your Author Service Manager. If you have an official letter from your university or institution showing that funds for your OA publication are unavailable, please attach that as well. The Waiver Request will normally be addressed within one week from the application date. All chapters that receive waivers or partial waivers will be designated as such online.
Feel free to contact us at funders@intechopen.com if you have any questions about Funding options or our Waiver program. If you have already begun the process and require further assistance, please contact your Author Service Manager, who is there to assist you!
\n\n
Note: All data represented above was collected by IntechOpen from 2013 to 2017.
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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null},{id:"27",title:"Multi-Agent Systems",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",isOpenForSubmission:!0,editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",slug:"mehmet-aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",biography:"Dr. Mehmet Emin Aydin is a Senior Lecturer with the Department of Computer Science and Creative Technology, the University of the West of England, Bristol, UK. His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. He has served as guest editor for a number of special issues of peer-reviewed international journals.",institutionString:null,institution:{name:"University of the West of England",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:19,paginationItems:[{id:"82196",title:"Multi-Features Assisted Age Invariant Face Recognition and Retrieval Using CNN with Scale Invariant Heat Kernel Signature",doi:"10.5772/intechopen.104944",signatures:"Kamarajugadda Kishore Kumar and Movva Pavani",slug:"multi-features-assisted-age-invariant-face-recognition-and-retrieval-using-cnn-with-scale-invariant-",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"82063",title:"Evaluating Similarities and Differences between Machine Learning and Traditional Statistical Modeling in Healthcare Analytics",doi:"10.5772/intechopen.105116",signatures:"Michele Bennett, Ewa J. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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