\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"1594",leadTitle:null,fullTitle:"Molecular Photochemistry - Various Aspects",title:"Molecular Photochemistry",subtitle:"Various Aspects",reviewType:"peer-reviewed",abstract:'There have been various comprehensive and stand-alone text books on the introduction to Molecular Photochemistry which provide crystal clear concepts on fundamental issues. 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These exciting chapters clearly indicate that the future of photochemistry like in any other burgeoning field is more exciting than the past.',isbn:null,printIsbn:"978-953-51-0446-9",pdfIsbn:"978-953-51-4990-3",doi:"10.5772/2058",price:119,priceEur:129,priceUsd:155,slug:"molecular-photochemistry-various-aspects",numberOfPages:296,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"de17d4df94b220132bdacf9e9d09d2d6",bookSignature:"Satyen Saha",publishedDate:"March 30th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/1594.jpg",numberOfDownloads:55568,numberOfWosCitations:85,numberOfCrossrefCitations:25,numberOfCrossrefCitationsByBook:3,numberOfDimensionsCitations:92,numberOfDimensionsCitationsByBook:4,hasAltmetrics:0,numberOfTotalCitations:202,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 23rd 2011",dateEndSecondStepPublish:"June 20th 2011",dateEndThirdStepPublish:"October 25th 2011",dateEndFourthStepPublish:"November 24th 2011",dateEndFifthStepPublish:"March 23rd 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7,10",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"54025",title:"Dr.",name:"Satyen",middleName:null,surname:"Saha",slug:"satyen-saha",fullName:"Satyen Saha",profilePictureURL:"https://mts.intechopen.com/storage/users/54025/images/2521_n.jpg",biography:"Born in Kolkata (formerly Calcutta) in India, Satyen Saha received B.Sc. 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It is time to abandon unethical or impossible to introduce into clinical pathways and look again at rudiments and face limitations. This book takes the reader from stem cell biology through clinical applications, ethics, law, and future possibilities. It is a solid base for every scientist interested in the topic of stem cells. Growing recognition of the limitations of stem cell therapies on the one hand and the rapidly increasing number of unethical therapies available in many countries force the quick establishment of the status quo of knowledge in a form accessible to all interested. This book is the answer to the multi-level and complex aspect of using stem cells in humans. It reveals real possibilities of introducing the latest research in the field of stem cell research. Material summarizes the ups and downs of this complex topic and shows the current trends in global markets and universities.
",isbn:"978-1-83768-033-7",printIsbn:"978-1-83768-032-0",pdfIsbn:"978-1-83768-034-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"13092df328080c762dd9157be18ca38c",bookSignature:"Ph.D. Diana Kitala",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11673.jpg",keywords:"Organoids, Organotypic Cultures, Pluripotent Stem Cells, Graft-Versus-Tumor, GvHD, Immunomodulation, Cell Transplant, Regenerative Medicine, Nanotechnology, Cell Environment, Law, Ethics",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 11th 2022",dateEndSecondStepPublish:"July 13th 2022",dateEndThirdStepPublish:"September 11th 2022",dateEndFourthStepPublish:"November 30th 2022",dateEndFifthStepPublish:"January 29th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A researcher involved in stem cell research from basic studies to clinical application (from GLP, through GMP to GCP). She worked for 10 years as GMP Head of Quality Assurance, at Dr. Stanisław Sakiel Burns Treatment Center, and as a University Lecturer. Assistant Professor Kitala is currently involved in writing national programs for medical research and evaluation of clinical research at the Medical Research Agency.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"203598",title:"Ph.D.",name:"Diana",middleName:null,surname:"Kitala",slug:"diana-kitala",fullName:"Diana Kitala",profilePictureURL:"https://mts.intechopen.com/storage/users/203598/images/system/203598.png",biography:"Assistant Professor Diana Paula Kitala graduated with degrees in Biotechnology and Biomedical Engineering, and while writing her doctoral thesis she completed postgraduate studies in the fields of clinical research, biostatistics, laboratory diagnostics, LEAN methodology, and Six Sigma management. She worked for 10 years in a tissue bank as GMP Head of Quality Assurance, in Dr. Stanisław Sakiel Burns Treatment Center, and as a university lecturer. She has taken part in scientific grants, and in 2019 she won the EWMA grant for the project 'Theory of constraints (TOC) and LEAN management for wider application of amniotic mesenchymal stem cells in a group of patients with chronic wounds.” She was nominated for the golden medal for merits for the Silesian Voivodeship. Now she is involved in writing national programs for medical research and evaluation of clinical research in Medcial research Agency. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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The research concerning both, structural and molecular studies, is based on two main data sources. The first source of information are patients with already formed aneurysm, and with well defined biochemical and morphological changes in aortic wall architecture. The other source of data are experimental studies based on laboratory animals with artificially induced aneurysms. This approach enables verification of various hypotheses concerning pathogenesis of aortic aneurysm. Regrettably, animal aneurysm models, although similar, are not exactly the same, as human pathology. Thus, since the link between both mentioned data sources is still lacking, the knowledge achieved to date, even being highly profound, is not sufficient to fully understand this disease. Besides well defined factors, predisposing to formation of aortic aneurysm (patient’s age, cigarette smoking, arterial hypertension, atherosclerosis, as well as the Marfan’s and the Ehlers-Danlos’s syndrome-associated mutations), increasing popularity is currently being gained by the hypothesis concerning the pivotal role of proteolytic enzymes - matrix metalloproteinases (MMPs) in aortic wall destruction. The involvement of MMPs in extracellular matrix damage in aortic aneurysm is doubtless. However, it needs to be elucidated, what the sequence of events is and what the exact role of MMPs is in these events. MMPs could play a role of “executioners”, that are produced and activated in the aortic wall as constituents of inflammatory reaction, in response to some yet poorly defined triggers. On the other hand, it is plausible, that aortic wall destruction, followed by inflammatory response to tissue degradation products, results from primary local overproduction and/or activation of proteases. It could be due to some mutations or polymorphisms of MMP genes, or some impairment in their controlling mechanisms. In that circumstance MMPs could rather be considered as “executors”, with causative role in aortic aneurysm pathogenesis. Although the majority of studies suggest the first scenario as being more possible, there is some evidence, that could support the second alternative, too.
\n\t\tThe histopathological assessment of aneurismal aortic wall specimens reveals widespread chronic inflammatory reaction. This reaction is associated with extensive destruction of elastic fibers in the tunica media layer, and infiltration of both, media and adventitia, by macrophages and lymphocytes, mainly the Th2 subset. Moreover, as has been found recently, outer media and adventitia of human aortic aneurysm samples contain numerous mast cells (Miyake & Morishita, 2009; Michel et al., 2011). In addition to the previously mentioned lymphocytes and macrophages, mast cells are currently recognized as a third considerable source of pro-inflammatory cytokines, including tumor necrosis factor (TNF), various chemokines, and interleukins. Furthermore, in cooperation with macrophages, mast cells produce and release large quantities of various proteases and, thus, they are also actively engaged in aortic wall destruction (Tsuruda et al., 2008). However, a trigger of inflammatory reaction still remains to be a missing component of this scenario.
\n\t\t\tRecently, it has been proposed, that the aneurysm pathogenesis could be explained, at least to some extent, by the model of chronic proteolytic atherothrombosis (Michel et al., 2011). This model is based on the observation that the development of aortic aneurysms is accompanied by the formation of chronic intraluminal thrombus inside the aneurysmal sac. It has been shown that the presence of intraluminal thrombus is associated with widespread degradation of elastic fibers, increased apoptosis and loss of vascular smooth muscle cells (VSMC) in tunica media, and with extensive inflammatory reaction in adventitia. It may suggest, that the thrombus rather, than the aortic wall, could be the primary source of various pro-inflammatory factors, including proteolytic enzymes (Michel et al., 2011). On the other hand, one can argue that formation of thrombus on the inner, luminal surface of the aortic wall could be secondary to already existing aortic wall inflammation, due to the damage of endothelium and tunica intima. Nevertheless, it is plausible, that independently of the sequence of events, the thrombus-aortic wall interface may be “the place, where the chaos begins”…
\n\t\t\t\tThe pathophysiological role of intraluminal thrombus may be described by various activities of its components. The first activity could be a generation of free radicals and induction of oxidative stress reaction, mainly due to a degradation of red blood cells and release of the potent pro-oxidant mediator – iron-rich hemoglobin. The oxidative stress leads to the production of reactive oxygen and reactive nitrogen species, which are both components of a self-augmenting mechanism (Miyake & Morishita, 2009). Reactive oxygen and nitric oxide increase expression of pro-inflammatory cytokines, followed by further up-regulation of reactive oxygen species production, peroxidation of membrane phospholipids and generation of eicosanoids and pro-apoptotic ceramides. Finally, reactive oxygen species induce activation of nuclear factor kappa-B (NF-κB), that leads to additional increase in MMPs expression and initiates the apoptosis of VSMC in the aortic wall. In addition to erythrocytes, intraluminal thrombus consists of an approximately 12-fold higher number of neutrophils, as compared to circulating blood (Michel et al., 2011). These cells produce a large number of proteinases, including elastase, cathepsin, MMP-8 and -9. Moreover, strong proteolytic activity between the thrombus and the adjacent aneurysm wall is revealed by the plasmin. This activity, although originally aimed at the thrombus fibrin network, may also contribute to aortic wall destruction. It may occur mainly through degradation of fibronectin, thus resulting in mesenchymal cells detachment and apoptosis, as well as direct activation of pro-MMPs.
\n\t\t\tAccording to “infection hypothesis”, the chronic inflammatory reaction, which takes place in the aortic wall, may be initiated by some pathogens. However, studies focusing on the presumed importance of various
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases, or matrixins, belong to the large and still expanding family of zinc endoproteinases. The members of this evolutionarily ancient group were found in various organisms, from bacteria and plants, through hydra and worms, to humans. So far, at least 25 distinct MMPs have been identified in vertebrates. In humans a presence of 23 proteins, encoded for 24 distinct genes, has been confirmed. This discrepancy is due to the fact that human MMP-23 was found to be encoded by two identical genes located on chromosome 1. Together with the astacins, the adamalysins, and large bacterial proteinases – serralysins, MMPs constitute a huge superfamily of enzymes, called metzincins, which are characterized by the presence of the zinc-binding motif, with a conserved methionine nearby.
\n\t\t\tMMPs play a crucial role in extracellular matrix (ECM) turnover. They are able to cleave main ECM components, including collagens, elastin, fibronectin, gelatin and aggrecan, as well as a variety of non-ECM molecules – transforming growth factor (TGF)-β, pro-IL-1β, pro-IL-8, Fas ligand, and pro-TNF. Moreover, MMPs are responsible for the release of cryptic fragments and neo-epitopes from extracellular matrix and non-ECM macromolecules, which may reveal bioactivities different from those of the parent molecules. Furthermore, MMPs may liberate numerous growth factors (e.g. vascular endothelial growth factor – VEGF and TGF-β) and cytokines, which are embedded in extracellular matrix and require proteolytic release from binding proteins for their activation. Finally, MMPs may modify cells’ attachment to the ECM by processing of syndecans, dystroglycan and other adhesion molecules (Endo et al., 2003; Yamada et al., 2001; Mott & Werb, 2004). These properties of MMPs make them key players in the majority of physiological conditions (e.g. pregnancy, embryogenesis, wound healing), but also in various pathologies, including cancer progression with metastases, liver fibrosis, periodontal disease, multiple sclerosis and vascular diseases, especially atherosclerosis and aortic aneurysm (Hadler-Olsen et al., 2011).
\n\t\t\tAs mentioned previously, MMPs should not only be recognized as typical effector/”executioner” molecules, but also, at least in some circumstances, they may be considered as real causative factors/”executors”. This status may be supported by results of studies concerning the genetic polymorphisms of MMP genes. The polymorphisms are natural differences in DNA sequence that occur in more than 1% of the entire population. The vast majority of them concern variability of single nucleotides and are known as single nucleotide polymorphisms (SNPs). The effect of particular SNP is determined by its position in a gene structure. Most SNPs are functionally neutral. However, some of them may lead to an amino acid substitution, thus influencing the structure and properties of encoded protein. Furthermore, some SNPs located in a promoter region may alter the level of gene transcription. There is the reason, for which functional SNPs may contribute to the individual susceptibility to common diseases, including aortic aneurysms. In this chapter authors will shortly review several polymorphisms of selected MMP genes, which have been suspected of being involved in aortic aneurysm development.
\n\t\t\tThe overall scheme of a protein structure is common among all MMPs, with more or less significant differences between particular groups (Fig. 1).
\n\t\t\t\tThe schematic structure of MMPs family
In general, on its N-terminus the MMP molecule contains a signal sequence, which directs the protein to the secretory pathway, and is removed during insertion of the protein into an endoplasmic reticulum. The signal sequence is followed by the propeptide composed of approximately 80 amino acid residues, that contains a characteristic conserved PRCGXPD motif, known as “cysteine-switch”. The role of this sequence is to block a catalytic zinc and thus maintain the latent form of an enzyme. The next, the catalytic domain, has a sphere-like shape with an active site containing two atoms of zinc inside a large, shallow cleft. The catalytic domain is composed of approximately 160-170 amino acids, with a unique HEXXHXXGXXH sequence, that binds zinc ions. The last, approximately 200 amino acid residues-long C-terminal domain, called the hemopexin-like domain is found in all MMPs except for MMP-7, -23 and -26. In most MMPs the hemopexin-like domain is linked to a catalytic domain through a short, approximately 10-30 amino acid residues-containing hinge region. Exceptionally, the hinge region of MMP-9 is 64 amino acids-long, and is strongly O-glycosylated. Furthermore, six representatives of the membrane type (MT) MMPs subgroup hold either a type I transmembrane domain with a short intracellular segment (MT1, -2, -3 and -5-MMP) or a cell membrane-anchoring glycosylphosphatidylinositol (GPI) moiety (MT4- and -6-MMP).
\n\t\t\t\tUnlike other MMPs, in the MMP-23 molecule, a cystein-rich segment with an immunoglobulin-like domain is present, instead of the hemopexin-like domain on C-terminus, whereas the N-terminal signal peptide has been replaced by an N-terminal type II transmembrane domain. In addition to the previously mentioned common components, other elements, attached to the catalytic domain are fibronectin II-like inserts, which are found in MMP-2 and -9 molecules exclusively. Furthermore, three of the secreted MMPs (MMP-11, -21 and -28), as well as all the membrane-anchored MMPs, have a unique sequence R(X/R)KR between the prodomain and the catalytic domain. This motif is recognized and cleaved by a serine proteinase – furin, that results in removal of prodomain from the active site of the catalytic domain, followed by intracellular activation of mentioned MMPs (Fanjul-Fernandez et al., 2010;).
\n\t\t\tTraditionally, MMPs were classified into 6 main groups – collagenases, gellatinases, stromelysins, matrilysins, membrane type MMPs and others, unclassified to former groups. However, increasing knowledge, concerning the molecular structure, substrate specificity and mechanism of MMPs activation contributed to an arrangement of their new classification. According to this classification, MMPs are divided into four groups: archetypal MMPs, matrilysins, gelatinases and furin-activated MMPs (Fanjul-Fernandez et al., 2010, Hadler-Olsen et al., 2011)
\n\t\t\t\tArchetypal MMPs have the structure typical for all MMPs. They are further divided into three subgroups: collagenases, stromelysins and other archetypal MMPs.
\n\t\t\t\t\tThis subgroup of archetypal MMPs is represented by three enzymes: collagenase-1 (MMP-1), collagenase-2 (MMP-8), and collagenase-3 (MMP-13). Their main common feature is the ability to cleave native collagens into characteristic N-terminal ¾ and C-terminal ¼ fragments (Fanjul-Fernandez et al., 2010). Since the triple helix conformation of native collagens is highly resistant to cleavage mediated by other proteinases, collagenases are crucial enzymes for initiation of collagen degradation. After the cleavage mediated by collagenases, the native collagens rapidly denature to gelatin and thus they become susceptible to degradation by other MMPs.
\n\t\t\t\t\t\tBesides the native fibrillar collagens (types I, II, III, V, and XI), the other targets for collagenases are numerous extracellular matrix components, as well as non-ECM molecules, including IL-8, pro-TNF, protease-activated receptor-1, several insulin-like growth factor-binding proteins (IGFBPs), etc… (Gearing et al., 1994; Boire et al., 2005; Amalinei et al., 2007).
\n\t\t\t\t\t\tThe activation of MMP-1 requires a presence of active MMP-3 or plasminogen activator/plasmin system. The main sources of collagenases are stimulated fibroblasts (MMP-1), neutrophils (MMP-8) and VSMC (MMP-1 and MMP-13). Increased levels of mRNA and proteins for collagenases were found in aortic aneurysm tissue (Kadoglou & Liapis, 2004). Moreover, they are supposed to be involved in aneurysm rupture.
\n\t\t\t\t\t\tThe studies focused on a presumable connection between aortic aneurysm formation and known SNPs in genes encoding for collagenases, including potentially clinically relevant SNP in MMP-1 promoter region (-1607 G/GG), did not reveal any significant correlation (Ogata et al., 2004; Sandford et al., 2007; Saratzis et al., 2011).
\n\t\t\t\t\tThe members of this group are stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10). Both stromelysins have a structure analogous to that of collagenases, however, in contrast to those enzymes, stromelysins are not able to cleave native collagen. Their substrates include processed collagen types III, IV, V, IX and X, laminin, gelatin, fibronectin, proteoglycans and several other molecules, e.g. plasminogen, fibrinogen and IL-1β (Amalinei et al., 2007). Although both stromelysins display similar substrate specificity, MMP-3 reveals a grater proteolytic activity, as compared to MMP-10. Furthermore, MMP-3 is known to activate various pro-MMPs (collagenases and gelatinases) by removal of their pro-domain, and therefore it is crucial for their activation (Suzuki et al., 1990; Visse & Nagase, 2003). Stromelysins may be produced by fibroblasts and epithelial cells, however, in aortic aneurysm tissue their main source seem to be macrophages (Fanjul-Fernandez et al., 2010).
\n\t\t\t\t\t\tThe possible clinical relevance of nucleotide polymorphism in promoter region of genes encoding for both, MMP-3 and MMP-10, has been studied by several authors (Sandford et al., 2007; Saratzis et al., 2011). It has been found, that in the MMP-3 promoter, at the position -1171, corresponding to the transcriptional start site, two variants – one of them, containing 5 adenosines (5A) and the other one with 6 adenosines (6A), may be present.
Interestingly, the 6A/6A variant carriers displayed a higher growth rate of atherosclerotic plaque, which, on the other hand, was more stable, than in patients with the 5A allele. Yoon and coauthors have observed a trend (p=0.06) for a higher 5A allele frequency in a small cohort of 47 Finnish patients with abdominal aortic aneurysm (Yoon et al., 1999). The higher 5A allele frequency among aortic aneurysm-suffering patients compared to a control group was also confirmed in a British population (Ye, 2006).
\n\t\t\t\t\t\tIn contrast to MMP-3, studies concerning the presumable role of MMP-10 gene polymorphisms, including -180 A/G SNP, have failed to reveal any significant correlation with a prevalence of aortic aneurysm (Ogata et al., 2005).
\n\t\t\t\t\tThis subgroup of archetypal MMPs includes four enzymes: MMP-12, MMP-19, MMP-20 and MMP-27. The representative of this subgroup – MMP-12, also known as macrophage metalloelastase, is mainly expressed and secreted by activated macrophages and is necessary for its migration (Visse & Nagase, 2003; Kadoglou & Liapis, 2004). The main substrate for MMP-12 is elastin, but the enzyme may cleave some other ECM molecules, including aggrecan, fibronectin, laminin, and type IV collagen.
\n\t\t\t\t\t\tThe increased expression of MMP-12 was found exclusively in aortic aneurysm wall, but not in the control, or atherosclerotic aorta specimens. Immunohistochemical studies have localized MMP-12 within the media of aortic aneurysms, predominantly in zones adjacent to non-dilated aorta. However, although MMP-12 is recognized as a key player in aneurysm formation, its prominent role has been neglected in the elastase-induced aneurysm animal model. Interestingly, it has been found that MMP-12-deficient mice revealed aortic dilatation similar to that of wild type animals, whereas mice lacking MMP-9 were resistant to aneurysm induction. Therefore, it was suggested that MMP-12 role is restricted rather to supporting other MMPs in aneurysm formation (Kadoglou & Liapis, 2004).
\n\t\t\t\t\t\tThe analysis of polymorphic sites in the MMP-12 gene and
Group | \n\t\t\t\t\t\t\t\t\tSubgroup | \n\t\t\t\t\t\t\t\t\tMMP | \n\t\t\t\t\t\t\t\t\tCommon name | \n\t\t\t\t\t\t\t\t\tSubstrates | \n\t\t\t\t\t\t\t\t|
ECM | \n\t\t\t\t\t\t\t\t\tNon-ECM | \n\t\t\t\t\t\t\t\t||||
Archetypal MMPs | \n\t\t\t\t\t\t\t\t\tCollagenases | \n\t\t\t\t\t\t\t\t\tMMP-1 | \n\t\t\t\t\t\t\t\t\tCollagenase-1 | \n\t\t\t\t\t\t\t\t\tCollagens (I, II, III, VII, VIII and X), gelatin, proteoglycan link protein, aggrecan, veriscan, tenacin, entactin | \n\t\t\t\t\t\t\t\t\tα1-PI, ILb-1, pro-TNF, IGFBP-3, MMP-2, MMP-9 | \n\t\t\t\t\t\t\t\t
MMP-8 | \n\t\t\t\t\t\t\t\t\tCollagenase-2 | \n\t\t\t\t\t\t\t\t\tCollagens (I, II, III, V, VII, VIII and X), gelatin, aggrecan | \n\t\t\t\t\t\t\t\t\tα1-PI, α2-antiplasmin, fibronectin | \n\t\t\t\t\t\t\t\t||
MMP-13 | \n\t\t\t\t\t\t\t\t\tCollagenase-3 | \n\t\t\t\t\t\t\t\t\tCollagens (I, II, III, IV, IX, X, XIV), gelatin, aggrecan, perlecan, large tenascin-C, fibronectin, osteonectin | \n\t\t\t\t\t\t\t\t\tMMP-9, plasminogen activator inhibitor-2 | \n\t\t\t\t\t\t\t\t||
Stromelysins | \n\t\t\t\t\t\t\t\t\tMMP-3 | \n\t\t\t\t\t\t\t\t\tStromelysin-1 | \n\t\t\t\t\t\t\t\t\tCollagens (III, IV, V and IX), gelatin, aggrecan versican, hyaluronidase-treated versican, perle- can, decorin, proteoglycan link protein, large tenascin-C, fibronectin, laminin, entactin, osteonectin | \n\t\t\t\t\t\t\t\t\tα1-PI, antithrombin-III, ovosstatin, substance P, IL-1β, serum amyloid A, IGFBP-3, fibrinogen and cross- linked fibrin, plasminogen, MMP-2/TIMP-2 complex MMP-1,-7,-8,-9,-13 | \n\t\t\t\t\t\t\t\t|
MMP-10 | \n\t\t\t\t\t\t\t\t\tStromelysin-2 | \n\t\t\t\t\t\t\t\t\tCollagens (III, IV and V), gelatin, casein, aggrecan, elastin, proteoglycan link protein | \n\t\t\t\t\t\t\t\t\tMMP-1,-8 | \n\t\t\t\t\t\t\t\t||
Other Archetypal | \n\t\t\t\t\t\t\t\t\tMMP-12 | \n\t\t\t\t\t\t\t\t\tMetalloelastase | \n\t\t\t\t\t\t\t\t\tCollagen IV, gelatin, elastin, casein, laminin, proteoglycan monomer, fibronectin, vitronectin, enactin | \n\t\t\t\t\t\t\t\t\tα1-PI, fibrinogen, fibrin, fibrin, plasminogen, myelin basic protein | \n\t\t\t\t\t\t\t\t|
MMP-19 | \n\t\t\t\t\t\t\t\t\tRASI | \n\t\t\t\t\t\t\t\t\tGelatin | \n\t\t\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t\t||
MMP-20 | \n\t\t\t\t\t\t\t\t\tEnamelysin | \n\t\t\t\t\t\t\t\t\tAmelogenin | \n\t\t\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t\t||
MMP-27 | \n\t\t\t\t\t\t\t\t\t- ND | \n\t\t\t\t\t\t\t\t||||
Matrilysins | \n\t\t\t\t\t\t\t\t\tMMP-7 | \n\t\t\t\t\t\t\t\t\tMatrilysin | \n\t\t\t\t\t\t\t\t\tCollagens IV and X, gelatin, aggrecan, decorin, proteoglycan link protein, fibronectin, laminin, insoluble fibronectin fibrils, entactin, large and small tenascin-C, osteonectin, β4 integrin, elastin, casein, transferrin | \n\t\t\t\t\t\t\t\t\tMMP-1,-2,-9 α1-PI, MMP-9/TIMP-1 complex, plasminogen | \n\t\t\t\t\t\t\t\t|
MMP-26 | \n\t\t\t\t\t\t\t\t\tMatrilysin-2 | \n\t\t\t\t\t\t\t\t\tCollagen IV, gelatin, fibronectin | \n\t\t\t\t\t\t\t\t\tProMMP-9, fibrinogen, α1-PI | \n\t\t\t\t\t\t\t\t||
ND-not determined \n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t
Matrilysins are represented by matrilysin-1 (MMP-7) and matrilysin-2 (MMP-26, or endometase). The most prominent feature of matrilysins group members is the lack of the hemopexin domain. MMP-26 is the smallest known MMP; it is composed of only 261 amino acids and may activate itself by autocatalysis. Matrilysins play an important role in degradation of ECM molecules, including type IV collagen, laminin, entactin, as well as several cell surface molecules, e.g. Fas ligand, E-cadherin and syndecan-1 (Fanjul-Fernandez et al., 2010). Due to a shedding of membrane-bound Fas ligand and generation of its soluble form, matrilysins may stimulate apoptosis. Furthermore, while cleaving plasminogen to produce an angiostatin fragments, matrilysins are involved in inhibition of angiogenesis. Interestingly, MMP-26 has an ability to activate pro-MMP-9 in a specific site, that results in better stability of MMP-9 (Zhaoet al., 2003; Amalinei et al., 2007). Moreover, intracellular MMP-26 was found to process the estrogen receptor β, therefore in patients with breast cancer an increased MMP-26 level was found to correlate with longer survival (Hadler-Olsen et al., 2011 )
\n\t\t\t\t\tThe group of gelatinases consists of two members: gelatinase A (MMP-2) and gelatinase B (MMP-9). Both of them are constitutively expressed by many cells, including fibroblasts, keratinocytes, endothelial cells, polymorphonuclear leukocytes, monocytes, alveolar macrophages and osteoclasts. When compared to other MMPs, the most significant difference in the structure of gelatinases is the presence of three type II fibronectin-like repeats within the catalytic domain. They are responsible for recognition and binding of denatured collagen and gelatin molecules (Visse & Nagase, 2003). Gelatinases may cleave various extracellular matrix molecules, e.g. collagen types I, IV, V, VII, IX, X, elastin, fibronectin, aggrecan, vitronectin, laminin, as well as numerous non-ECM molecules, including pro-TNF, TGF-β, pro-IL-1β and pro-IL-8 (Fanjul-Fernandez et al., 2010). Moreover, they are involved in generation of several pro- and anti-angiogenic factors, which may originate from both, ECM and non-ECM substrates (Mott & Werb, 2004).
\n\t\t\t\t\tGelatinases are considered the most important members of the MMPs family, involved in pathogenesis of aortic aneurysm. The amounts of mRNA and specific proteins in the aneurysm wall, as well, as plasma levels of both, MMP-2 and MMP-9, were statistically significantly higher in patients with aortic aneurysms, as compared to healthy controls. Moreover, it has been found that plasma levels of gelatinases noticeably correlate with aneurysm expansion rate and therefore they were suggested as presumable predictors of the aneurysm rupture risk. In an animal experimental study it was proven, that infusion of gelatinases resulted in development of aortic aneurysms. Interestingly, MMP-2- and/or MMP-9-deficient mice were resistant to aneurysm formation in this model (Longo et al., 2002; Baxter, 2004; Kadoglou & Liapis, 2004).
\n\t\t\t\t\tRecently, it has been postulated, that, in addition to elastin degradation, gelatinases may also be engaged in the pathogenesis of aortic aneurysm in a proteolysis-independent fashion. This hypothesis is based on the observation, that both, MMP-2 and MMP-9, may display some inhibitory influence on the calcium-dependent contraction of VSMC isolated from the aortic wall (Raffetto & Khalil, 2008). In addition to maintenance of aortic wall integrity, the contraction of those cells is considered as a counterbalance of hemodynamic forces, that protects the aorta against dilatation during each cardiac cycle. Thus, the MMP-mediated reversible inhibition of vascular myocytes contraction could promote aneurysm progression. However, this issue requires further elucidation.
\n\t\t\t\t\tMMP-2, or gellatinase A, is constitutively expressed by vascular myocytes, however, it may be produced in small amounts by macrophages and fibroblasts, too. As described in chapter 3.4, the activation of MMP-2 occurs mainly by its interaction with MT1-MMP/TIMP-2. Due to its elastolytic activity, MMP-2 is believed to play a pivotal role in aortic aneurysm development. It was found, that VSMC isolated from aortic aneurysm tissue produced higher amounts of MMP-2, as compared to those from atherosclerotic, or normal aortic wall. Surprisingly, the activity of MMP-2 negatively correlated with aneurysms diameter. This observation could support the opinion, that MMP-2 may be essential in the early stages of aneurysm development. Besides weakness of the aortic wall, MMP-2-mediated degradation of elastic fibers may lead to production of elastin-derived peptides, which have a great chemotactic potential. These peptides may promote recruitment of inflammatory cells and enhance further proteolysis. Moreover, MMP-2 liberates TGF-β from an inactive extracellular complex consisting of TGF-β, latent TGF-β binding protein and TGF-β-latency associated protein, which may stimulate various MMPs expression and results in further progression of the disease (Rizas et al., 2009).
\n\t\t\t\t\t\tAmong 18 polymorphisms found in the MMP-2 gene, the SNP located in a promoter (-1306 C/T) was initially considered as clinically relevant. The studies focusing on the influence of this particular SNP on promoter function have shown, that the presence of C allele was associated with a higher promoter activity (Price et al., 2001). However, none of clinical studies, addressed at verifying a possible correlation between -1306 C/T SNP and aortic aneurysm prevalence, has revealed such a connection (Eriksson et al., 2005; Ogata et al., 2005; Sandford et al., 2007; Saratzis et al., 2011).
\n\t\t\t\t\tMMP-9, or gellatinase B, is mainly produced by macrophages and neutrophils. Subsequently to proteolytic activation by a variety of factors, including plasminogen activators and other MMPs (MMP-2, -3, -12), MMP-9 displays elastolytic, collagenolytic and gelatinolytic activity. The leader position of MMP-9 in the pathogenesis of aortic aneurysm may be confirmed by several observations. Animal studies have shown, that MMP-9-deficient mice were resistant to experimentally induced aortic dilation and they did not reveal elastin degradation despite the presence of inflammatory cell in the aortic wall (Kadoglou & Liapis, 2004; Baxter, 2004). On the other hand, among all metalloproteinases, MMP-9 is the most abundantly expressed enzyme in aortic aneurysm wall, in contrast to normal aortic tissue, where it was not present. Also, huge amounts of MMP-9 are released by neutrophils trapped in the intraluminal thrombus (see also chapter 2.1). Furthermore, high MMP-9 concentrations were detected in ruptured aneurysms. However, although patients with an aortic aneurysm have significantly higher levels of MMP-9, than control individuals, there is no consensus regarding a direct correlation between MMP-9 plasma levels and aneurysm progression and rupture risk to date (Takagi et al., 2009; Eugster et al., 2005). Therefore, this issue still requires further elucidation.
\n\t\t\t\t\t\tSeveral polymorphisms have been found in the MMP-9 gene. Most of the studies have focused on -1562 C/T polymorphism in a promoter region. It has been proven that a common T to C substitution in -1562 position of the MMP-9 promoter is associated with approximately 50% increase of the promoter activity. A clinical study by Medley and coauthors has shown that mRNA level, protein concentration, as well as enzymatic activity of MMP-9 in aortic aneurysm tissues of -1562 T allele carriers were significantly higher, as compared to those with the -1562 C variant. Also, plasma levels of MMP-9 were much higher in -1562 T carriers, than in patients with -1562 C allele (Medley et al., 2004). Furthermore, Jones and coauthors have also reported a higher frequency of the -1562 T variant in a group of patients with aortic aneurysm (n=414), in comparison to individuals with atherosclerotic peripheral vascular disease (n=172, adjusted odds ratio 2.94), or healthy control subjects (n=203, adjusted odds ratio 2.41) (Jones et al., 2003).
\n\t\t\t\t\t\tInterestingly, subsequent studies, independently conducted by Ogata and Eriksson on large groups of aortic aneurysm-suffering individuals (n=387 and n=455, respectively) have failed to confirm this association (Ogata et al., 2005; Eriksson et al., 2005). In a large study by Smallwood and coauthors, carried out on 678 patients with aortic aneurysms and 659 healthy controls, no statistically significant association between occurrence of the -1562 T allele and development of aortic aneurysm was found (Sandford et al., 2007; Smallwood et al., 2008; Saratzis et al., 2011).
\n\t\t\t\t\t\tIt is noteworthy, that although recent studies have negated the direct involvement of -1562 C/T polymorphism in pathogenesis of aortic aneurysm, the potential importance of other functional polymorphisms in the MMP-9 gene cannot be excluded. Presumably, two additional functional SNPs – the first located in the exon encoding for catalytic domain (Q279R), and the next relating to the sequence encoding for hemopexin domain (P574R), could be considered as attractive candidates for further studies.
\n\t\t\t\t\tThe members of this group are characterized by the presence of an unique RXKR or RRKR sequence, inserted between the prodomain and the catalytic domain. This site is recognized and cleaved by pro-protein convertases or serine proteinases – furins, thus resulting in an activation of enzyme. The furin-activated MMPs are further divided into small subgroups: secreted MMPs, membrane-type I and type II MMPs and GPI-anchored MMPs (Fu et al., 2008; Fanjul-Fernandez et al., 2010).
\n\t\t\t\t\tThe furin-activated secreted MMPs include MMP-11, MMP-21 and MMP-28. In contrast to other secreted MMPs, members of this subgroup undergo intracellular processing by furin, or furin-like proteases and therefore they are secreted already in active form (Fanjul-Fernandez et al., 2010).
\n\t\t\t\t\tAll the membrane type MMPs (MT-MMPs) contain a hydrophobic component that enables their insertion in the cell membrane. They control the close neighborhood of both, normal and pathological cells, thus being involved in promoting of cell migration, invasion, experimental metastasis and angiogenesis (Hernandez-Barrantes et al., 2002).
\n\t\t\t\t\t\tType I transmembrane MMPs include: MT1-, MT2-, MT3-, and MT5-MMP (MMP-14, -15, -16, and -24, respectively). They are characterized by a long hydrophobic transmembrane sequence followed by a short cytoplasmic tail, which could participate in several signaling pathways. The main representative of this subgroup, MT1-MMP (MMP-14) may be expressed on the cell surface of various cells, however, activated macrophages and VSMC are considered as its most important producers. It may cleave native type I collagen into ¾ – ¼ fragments in a collagenase-specific fashion. Apart from collagen I, MT1-MMP is able to process various components of extracellular matrix, including collagens type II and III, gelatin, fibronectin, as well, as non-ECM molecules, e.g. hyaluronan receptor (CD44), myelin-inhibitory protein and α-2 macroglobulin (Fanjul-Fernandez et al., 2010). Furthermore, as previously mentioned, MT1-MMP plays a key role in the proteolytic activation of pro-MMP-2 (see chapter 3.4).
\n\t\t\t\t\t\tGroup | \n\t\t\t\t\t\t\t\t\tSubgroup | \n\t\t\t\t\t\t\t\t\tMMP | \n\t\t\t\t\t\t\t\t\tCommon name | \n\t\t\t\t\t\t\t\t\tSubstrates | \n\t\t\t\t\t\t\t\t|
Extracellular matrix (ECM) | \n\t\t\t\t\t\t\t\t\tNon-ECM | \n\t\t\t\t\t\t\t\t||||
Gelatinases | \n\t\t\t\t\t\t\t\t\tMMP-2 | \n\t\t\t\t\t\t\t\t\tGelatinase A | \n\t\t\t\t\t\t\t\t\tCollagens (I, IV, V, VII, X, XI and XIV), gelatin, elastin, fibronectin, laminin-1, laminin-5, galectin-3, aggrecan, decorin, hyaluronidase-treated versican, proteoglycan link protein, osteonectin | \n\t\t\t\t\t\t\t\t\tIL-1b, α1-PI, prolysyl oxidase fusion protein, MMP-1, MMP-9, MMP-13 | \n\t\t\t\t\t\t\t\t|
MMP-9 | \n\t\t\t\t\t\t\t\t\tGelatinase B | \n\t\t\t\t\t\t\t\t\tCollagens (IV, V, VII, X and XIV), gelatin, elastin, galectin-3, aggrecan, fibronectin, hyaluronidase-treated versican, proteoglycan link protein, entactin, osteonectin | \n\t\t\t\t\t\t\t\t\tα1-PI, IL-1β, plasminogen | \n\t\t\t\t\t\t\t\t||
Furin-activated MMPs | \n\t\t\t\t\t\t\t\t\tSecreted | \n\t\t\t\t\t\t\t\t\tMMP-11 | \n\t\t\t\t\t\t\t\t\tStromelysin-3 | \n\t\t\t\t\t\t\t\t\tCasein, laminin, fibronectin, gelatin, collagen IV and carboxymethylated transferrin | \n\t\t\t\t\t\t\t\t\tα1-PI, casein, IGFBP-1 | \n\t\t\t\t\t\t\t\t
MMP-21 | \n\t\t\t\t\t\t\t\t\tXMMP | \n\t\t\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t\t|||
MMP-28 | \n\t\t\t\t\t\t\t\t\tEpilysin | \n\t\t\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t\t|||
Type I transmembrane | \n\t\t\t\t\t\t\t\t\tMMP-14 | \n\t\t\t\t\t\t\t\t\tMT1-MMP | \n\t\t\t\t\t\t\t\t\tCollagens (I, II and III), casein, elastin, fibronectin, gelatin, laminin, vitronectin, large tenascin-C, entactin, proteoglycans | \n\t\t\t\t\t\t\t\t\tα1-PI, MMP-2,-13 | \n\t\t\t\t\t\t\t\t|
MMP-15 | \n\t\t\t\t\t\t\t\t\tMT2-MMP | \n\t\t\t\t\t\t\t\t\tLarge tenascin-C, fibronectin, laminin, entactin, aggrecan, perlecan | \n\t\t\t\t\t\t\t\t\tMMP-2 | \n\t\t\t\t\t\t\t\t||
MMP-16 | \n\t\t\t\t\t\t\t\t\tMT3-MMP | \n\t\t\t\t\t\t\t\t\tCollagen-III, gelatin, casein, fibronectin | \n\t\t\t\t\t\t\t\t\tMMP-2 | \n\t\t\t\t\t\t\t\t||
MMP-24 | \n\t\t\t\t\t\t\t\t\tMT5-MMP | \n\t\t\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t\t|||
GPI-anchored | \n\t\t\t\t\t\t\t\t\tMMP-17 | \n\t\t\t\t\t\t\t\t\tMT4-MMP | \n\t\t\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t\t||
MMP-25 | \n\t\t\t\t\t\t\t\t\tMT6-MMP | \n\t\t\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t\t|||
Type II transmenbrane | \n\t\t\t\t\t\t\t\t\tMMP-23A | \n\t\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t\t||
MMP-23B | \n\t\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t\t|||
ND – not determined \n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t
Recently, it was found, that mRNA and protein levels of MT-MMP-1 were significantly higher among patients with an aortic aneurysm, than in healthy controls or atherosclerosis-suffering subjects. Therefore, it is suggested, that MT-MMP-1 may also be important in pathogenesis of aortic aneurysm, especially due to its multidirectional action. Besides direct destruction of extracellular matrix components, MT1-MMP activates MMP-2 and facilitates migration of macrophages, thus promoting inflammatory infiltration of the aortic wall (Kadoglou & Liapis, 2004).
\n\t\t\t\t\t\tType II transmembrane MMPs are represented by enzymes: MMP-23A and MMP-23B, which, despite being encoded by two different genes, actually have an identical amino acid sequence. Their structure is significantly distinct from other MMPs, since they lack the signal peptide, the cysteine-switch motif and the hemopexin domain. Moreover, opposite to type I MT-MMPs, they have a transmembrane domain located in their N-terminal tail, whereas C-terminus contains a cysteine array and immunoglobulin-like domains (Fanjul-Fernandez et al., 2010).
\n\t\t\t\t\t\tThe last subgroup of MT-MMPs includes MT4-MMP and MT6-MMP (MMP-17 and -25, respectively). Both of them have the glycosylphosphatidylinositol (GPI) anchor instead of a transmembrane domain on their C-terminus, that enables binding of the MMP molecule to the cell membrane. To date, little is known about the presumable role of other MT-MMPs in pathogenesis of aortic aneurysm, with the exception of MT1-MMP, therefore, this subject still requires further studies.
\n\t\t\t\t\tThe critical role of MMPs in physiology, as well as their involvement in various pathological conditions decipher the tight control of production and activation of these enzymes. Among all MMPs, only MMP-2 and MMP-9 were found to be expressed constitutively, whereas the expression of the remaining members of the MMP family has to be induced, e.g. in response to a tissue remodeling, or inflammatory reaction. Numerous factors, including pro-inflammatory cytokines (IL-1β, IL-6, TNF, etc.), growth factors (platelet-derived growth factor – PDGF; epidermal growth factor – EGF; TGF-β; etc.) and corticosteroids are involved in the control of MMPs gene expression Kadoglou & Liapis, 2004; Diehm et al., 2007). The common feature of the majority of inducible genes, including these encoding for MMPs, is the presence of the binding sites for transcription factors AP-1 and/or NF-κB in their promoter region. AP-1 transcription factors are heterodimer complexes, composed of two proto-oncogene family proteins – Jun and Fos. Together with NF-κB, a p50/p65 heterodimer, which controls the expression of numerous immune response- and inflammation-engaged molecules, AP-1 complexes interconnect a number of growth factor- and cytokine-mediated pathways. Another group of transcription factors involved in regulation of MMPs expression are members of Ets family. They recognize and bind to the conserved polyomavirus enhancer activator protein-3 (Pea3) binding site, which is found in MMP promoters. Since the Pea3 binding site is located contiguously to at least one AP-1 element, the interaction between both transcription factors will presumably modulate promoter response to various stimuli. Most recently, it was suggested that, in addition to the formerly discussed, the modification of chromatin structure through its acetylation-deacetylation could be another mechanism, involved in the regulation of MMP genes expression. Interestingly, it has been found that inhibition of histone deacetylase (HDAC) results in enhanced MMP-3, but decreased MMP-1 and MMP-9 expression in response to stimulation with IL-1β or TNF (Clark et al., 2007; Clark et al., 2008). Therefore, this aspect of MMPs expression control remains unclear and requires further studies. The next issue to be clarified is the role of mechanotransduction and the involvement of putative mechanoreceptors or mechano-responsive elements in MMPs expression control. This pathway seems to be of great importance especially in tissues permanently exposed to dynamic stress, like joint cartilage chondrocytes or VSMC in blood vessels (Blain, 2007). Finally, it is noteworthy, that besides transcriptional level, MMPs expression in response to various stimuli, including cytokines and growth factors, may also be controlled by the modulation of specific mRNA stability (Chakraborti et al., 2003).
\n\t\t\t\tMost recently, it has been found that MMP-2 activity may also be modulated by protein kinase C–mediated phosphorylation at the post-translational level (Sariahmetoglu et al., 2007). This modification may involve at least 5 amino acid residues from active site of catalytic domain and may result in modulation of its activity. Possibly, 3′-5′ cyclic adenosine monophosphate (cAMP) pathway may be involved in this step, too.
\n\t\t\tAs mentioned previously, all MMPs are produced and secreted in an inactive zymogen form. This status is maintained due to the presence of the “cysteine-switch”, the particular interaction between the thiol group of the prodomain cysteine and the zinc ion from the catalytic domain. The disruption of this interaction is essential for enzyme activation and may occur in two different manners (Fig. 2).
\n\t\t\t\tThe first mode is an alteration of the cysteine thiol group by some physiological factors, including disulfides, oxidants and electrophiles, as well as non-physiological compounds, among them denaturing surfactants with sodium dodecyl sulphate (SDS), alkylating agents, organomercurials with 4-aminophenylmercuric acetate (APMA), and heavy metal ions. This alteration results in some allosteric changes in MMP structure, followed by an exposure of the catalytic site of the enzyme. It may lead to the auto-cleavage and removal of prodomain, and thus is associated with reduction of enzyme molecular size. On the other hand, the prodomain may stay attached to the active enzyme and thus the molecular weight of activated MMP remains unchanged (Fu et al., 2008; Hadler-Olsen et al., 2011) (Fig. 2A).
\n\t\t\t\tThe second mechanism of MMPs activation is direct cleavage of their prodomain by another proteolytic enzyme. It has been shown that proteolytic activation of MMPs may be conducted by other MMPs, as well as a broad spectrum of extracellular serine-, cysteine- or aspartate-proteinases. Moreover, this mechanism is also utilized during an intracellular activation of MMPs by furin, the subtilisin-like serine proteinase from the trans-Golgi network (Fig. 2A).
\n\t\t\t\tAn interesting combination of both, allosteric and proteolytic mode of action, represents activation of MMP-2 by the membrane type 1-MMP (MT1-MMP, or MMP-14) in the presence of the endogenous MMP inhibitor – the tissue inhibitor of MMPs (TIMP)-2. The TIMP-2 molecule serves as a link between MMP-2 and MMP-14, where the N-terminal part of TIMP-2 inactivates MMP-14 and its C-terminal part binds to the hemopexin domain of pro-MMP-2 (Fig. 2B). The prodomain of immobilized MMP-2 is then cleaved by another recruited MMP-14 molecule, thus resulting in proteolytic activation of MMP-2. Remarkably, other membrane type MMPs: MT2-MMP and MT3-MMP are able to activate pro-MMP-2 without involvement of TIMP (Hadler-Olsen et al., 2011, Klein & Bischoff, 2010).
\n\t\t\t\tThe MMP activation pathways (a detailed description in text)
When firmly supervised, matrix metalloproteinases control various physiological reactions very precisely. However, if this supervision appears incompetent, MMPs reveal their “dark side of the Force” and become highly dangerous molecules, which are engaged in many pathologies, including the development of an aortic aneurysm. Therefore, mechanisms responsible for this regulation and factors participating in these mechanisms are potentially useful in some therapeutic approaches.
\n\t\t\t\tStandard mechanisms of MMPs silencing include interaction with the specific tissue inhibitors of metalloproteinases and other endogenous inhibitors, such as α2-macroglobulin, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and tissue-factor-pathway-inhibitor 2 (TFPI2) (Maskos & Bode, 2003).
\n\t\t\t\tSurprisingly, although reactive oxygen species are known to activate autolytic cleavage of MMPs due to disruption of their “cysteine switch”, it has been suggested that oxidants may also inactivate MMPs by modification of some amino acids critical for their catalytic activity (Fu et al., 2008).
\n\t\t\t\tTissue inhibitors of metalloproteinases are secreted by different types of cells, including macrophages, VSMC and platelets. The basically defined function of TIMPs is a suppression of the MMPs activity by biding to their catalytic domain and blocking enzymatic activity. Based on
It is plausible, that functional polymorphisms in genes encoding for TIMPs could influence the activity of MMPs in the aneurysm wall. Thus, several SNPs supposed to affect the level of TIMP transcription, were assessed in patients with aortic aneurysms. It is noteworthy, that the genotyping results were analyzed for male and female patients separately due to the fact, that TIMP-1 gene is located on the X chromosome. To date, the association with aortic aneurysm has been suggested for two polymorphisms in gene for TIMP-1 (434 C/T and rs2070584 T/C) (Ogata et al., 2005) and two in TIMP-2 (a promoter SNP -479 C/T, and 573 G/A, but in male patients group only) (Wang et al., 1999; Hinterseher et al., 2007). Nevertheless, since the mentioned analyses concerned relatively small groups, this issue still requires additional investigation (Sandford et al., 2007; Saratzis et al., 2011).
\n\t\t\t\tSince the modulation of MMPs activity by endogenous inhibitors in pathology seems to be inefficient, several strategies with exogenous MMP modulators have been developed. It is noteworthy, that some of these modulators are already used in clinical practice, although the primary indication for their application did not concern inhibition of MMPs.
\n\t\t\t\t\tAn interesting approach may be the use of MMP-specific antibody-based inhibitors. The experimental model with neutralizing antibodies directed against MMP-2 has shown their protective influence on a heart exposed to ischemia/reperfusion injury (Cheung et al., 2000). However, the verification, whether this procedure would be useful in management of aortic aneurysms, needs further studies. Apart from endogenous inhibitors, various pharmacological agents may reveal inhibitory activity against MMPs. The small hydroxamate-based zinc-chelating synthetic agents, such as batimastat, marimastat or ilomastat (galardin), were first used in oncology, to suppress MMPs-dependent metastasis and tumor invasion. However, due to non-selective, generalized inhibition of MMPs activity with numerous adverse events, accompanied by relatively poor effectiveness, their clinical career was ended very soon (Baxter, 2004).
\n\t\t\t\t\tTetracyclines are natural antibiotics derived from
The beneficial influence of tetracyclines on aneurysm expansion rate may be multidirectional, including their antimicrobial activity against
The mechanism of anti-aneurysm protective action of macrolides remains unclear. Recently, another macrolide derivative, rapamycin, was tested in animal aortic aneurysm model. Due to its strong anti-inflammatory and immunosuppressive properties, rapamycin is commonly used to prevent transplanted organ rejection. It has been found, that rapamycin administration in experimentally induced aortic aneurysms in rat significantly inhibits activation of NF-κB and, subsequently, MMP-9 expression thus resulting in 40% decrease of aneurysm expansion rate, as compared to control animals (Lawrence et al., 2004).
\n\t\t\t\t\tThe inhibitors of hydroxymetylglutaryl-coenzyme A reductase, better known as statins, are widely used in a treatment of patients with cardiovascular diseases. Apart from their main activity, which decreases atherogenic lipoproteins, statins reveal various pleiotropic effects, including an augmentation of pro-apoptotic properties of some anticancer drugs, or an inhibition of inflammatory cell activity. Possibly, these anti-inflammatory properties of statins result from suppression of NF-κB, that is also involved in regulation of MMPs expression. Indeed,
Unfortunately, the issue concerning statins influence on aortic aneurysm progression seems unlikely to be resolved in the near future, because of two reasons at least. Firstly, the prevalence of statin use in aortic aneurysm-suffering patients is very high, mainly due to other concomitant cardiovascular diseases. Therefore, it may be difficult to assemble a control group for a large randomized study. Secondly, according to current recommendations, statins should be used as perioperative protection during open surgical, as well as endovascular aneurysm repair (Diehm et al. 2007). Thus, such a study, additionally to being difficult to design, appears to be ethically controversial.
\n\t\t\t\t\tAs was discussed previously (chapter 2.1), the aortic aneurysm is usually accompanied by an intraluminal thrombus, that is always associated with more or less clinically overt coagulation abnormalities. It has been shown, that these coagulopathies may be successfully treated with small doses of low molecular weight heparin (LMWH) (Jelenska et al., 2004). Moreover, our subsequent studies revealed, that in addition to the attenuation of coagulation abnormalities, a LMWH treatment resulted in statistically significant decrease of circulating MMP-9 plasma activity. Interestingly, the
Based on results of studies focused on molecular aspects of aortic aneurysm pathophysiology, the c-Jun N-terminal kinase (JNK) has been selected as a new target for therapy. Using pharmacological JNK inhibitor Yoshimura and coauthors prevented the development, or induced the regression of already formed aneurysm in calcium-, or angiotensin II-induced aortic aneurysm mouse models. This effect was associated with decreased MMP-9 activity, but also with restoration of aortic tissue architecture, mainly due to the upregulation of various extracellular matrix proteins synthesis. Obviously, the results of further studies are expected highly impatiently (Yoshimura et al., 2005; Miyake & Morishita, 2009).
\n\t\t\t\t\tRecently, it has been suggested, that the renin-angiotensin system and its main effector molecule – angiotensin II, may also be involved in the initiation of inflammatory reaction in the aortic wall and, thus, it significantly contributes to the development of aneurysm. Therefore, antagonists of the angiotensin II receptor were tested for their presumable protective effect on aneurysm progression. Indeed, it was shown, that losartan and valsartan, two representatives of the group, were effective in preventing aneurysm formation. Interestingly, although they do not appear to influence MMPs activity directly, their beneficial influence was associated with decrease of MMPs expression in aneurismal tissue, possibly due to the suppression of NF-κB-controlled inflammatory reaction (Fujiwara et al., 2008; Miyake & Morishita, 2009). However, since the career of angiotensin II receptor antagonists in a management of cardiovascular diseases is rather short, their value in aortic aneurysm treatment still remains to be verified.
\n\t\t\t\t\t\tThe next group of pharmaceuticals, addressed to interfere with the renin-angiotensin system are angiotensin converting enzyme (ACE) inhibitors. In contrast to the previously described angiotensin II receptor antagonists, they bind to the active site of MMPs and directly block their enzymatic activity in a dose dependent manner. Using animal models, it has been shown, that ACE inhibitors, including captopril, enalapril, lisinopril and perindopril, reduced the aortic wall degeneration and aneurysm progression. Surprisingly, data provided by several clinical trials are highly inconsistent. Reports by Lederle and Taylor, or Hackam group suggested independently, that patients with aortic aneurysms, which received ACE inhibitors, displayed lower aneurysm expansion rate and were better protected from aneurysm rupture, as compared to individuals treated without convertase inhibitors (Hackam et al., 2006; Lederle & Taylor, 2006). On the other hand, Schouten and colleagues did not find any correlation between aneurysm dilatation rate and ACE inhibitors (Schouten et al., 2006; Baxter et al., 2008; Miyake & Morishita, 2009). Moreover, the abdominal aortic aneurysm screening program in UK revealed an increasing aneurysm growth rate, that was apparently associated with ACE inhibitors intake (Sweeting et al., 2010). Therefore, this approach urgently needs further elucidation in multicenter prospective randomized trials, although, due to the common use of ACE inhibitors in cardiovascular diseases, the study design will possibly meet similar obstacles, as in statins case.
\n\t\t\t\t\tRecently, the novel strategy based on targeting transcription factors, which are known to be involved in regulation of inflammatory reaction and MMPs expression, appears to be highly promising approach in the management of aortic aneurysm. A principle of this strategy is the use of synthetic oligodeoxynucleotides (ODNs), referred as “decoy” ODNs, which specifically recognize and bind to respective transcription factors and thus competitively block their binding to promoter of gene of interest.
\n\t\t\t\t\t\tThis decoy strategy was used to inhibit two transcription factors – NF-κB and ets-1, which are suggested to control gene expression of several MMPs, including MMP-1, -2, -3 and -9. Using elastase-induced aneurysm rat and rabbit models, and chimeric anti-NF-κB/ets-1 decoy ODNs, Miyake and colleagues have analyzed the effects of the simultaneous suppression of both, NF-κB and ets-1. They found, that this approach resulted in marked decrease of aortic aneurysm progression, that was accompanied by significant decrease of MMP-1 and MMP-9 expression in the aneurysm wall. Moreover, in the rabbit model the application of the mentioned decoy system onto already formed aneurysms led to their significant regression, which in addition to MMPs inhibition, was possibly due to induction of collagen and elastin synthesis, that is negatively controlled by ets-1. Hopefully, this strategy will be effective also in human, since the anti-NF-κB/ets-1 ODNs decreased MMPs expression in
The increasing evidence concerning the involvement of MMPs in various pathologies, including aortic aneurysm, results in the necessity to develop methods of analysis that would be sufficiently sensitive and specific enough to detect minute amounts of MMPs.
\n\t\t\t\tThe above mentioned main requirements are met by an enzyme-linked immunosorbent assay (ELISA). Despite its high sensitivity (picograms per ml) and availability for all known MMPs, the ELISA method provides data reflecting only the specific protein amount, without any information about its enzymatic activity. This obstacle is partially resolved by a new generation of ELISA kits, that can discriminate between full length pro-enzyme and proteolytically activated MMP (Fig. 3A). Obviously, similar data could be obtained using the western-blot method with respective anti-MMP antibodies. Nevertheless, the previously mentioned non-proteolytic activation of full-length molecules may result in false negative, or at least, underestimated results of MMP measurement. Thus, the studies focusing on MMPs require another method that would enable convenient analysis of their enzymatic activity.
\n\t\t\t\tCurrently, the standard method used for the analysis of MMPs activity is a substrate-specific zymography with sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis (PAGE). The method is based on a molecular size-dependent electrophoretic separation of tested samples in a polyacrylamide gel, containing substrate specific for MMP being analyzed, e.g. gelatin for MMP-2 and MMP-9, casein for MMP-1, -3, -7, -10, -12 and -13 or collagen for MMP-1 and -13 (Kupai et al., 2010). Then, the gel is incubated in zinc- and calcium-rich reaction buffer to re-activate enzyme particles separated in the gel. The high local concentration of enzyme molecules results in a substrate digestion, that is restricted to the area close to the position of respective MMP in the gel. The visualization of enzymatic activity of assayed samples occurs after incubation of the whole gel with the staining solution, e.g. Coomassie blue. The presence of an unstained area in a gel corresponds to a substrate cleavage, due to enzymatic activity of respective MMP, whereas the size of this area directly correlates with amount and/or activity of the enzyme. Thus, the standard SDS-PAGE zymography allows a semi-quantitative comparison of respective MMP amount, or more precisely – activity between various samples. When used with known amounts of recombinant MMP, as a reference, the method permits the quantitative assessment of respective MMP. Furthermore, due to the gel electrophoresis of analyzed samples, this method enables the molecular size-based identification and individual measurement of both, full length pro-MMP and its short processed form, too (Fig. 3D, also Fig.2). It has been proven that sensitivity of standard SDS-PAGE zymography is sufficient to detect similar amounts of active MMP, as those using ELISA method (Table 1).
\n\t\t\t\t\tSubstrate | \n\t\t\t\t\t\t\t\tEnzyme | \n\t\t\t\t\t\t\t\tDetection limit | \n\t\t\t\t\t\t\t
gelatin | \n\t\t\t\t\t\t\t\tMMP-2 | \n\t\t\t\t\t\t\t\t10 pg | \n\t\t\t\t\t\t\t
casein | \n\t\t\t\t\t\t\t\tMMP-7 | \n\t\t\t\t\t\t\t\t1 ng | \n\t\t\t\t\t\t\t
collagen | \n\t\t\t\t\t\t\t\tMMP-1 | \n\t\t\t\t\t\t\t\t0.1 pg | \n\t\t\t\t\t\t\t
Examples of SDS-PAGE zymography detection limits (Kupai et al., 2010)
It is noteworthy, that the standard SDS-PAGE zymography is not free of some problems, either. The important issue is the unspecific, SDS-mediated activation of pro-MMP, that may occur during electrophoresis. Obviously, this event affects the results, and is usually associated with an overestimation of MMP activity. Additional difficulty with the use of this method is the long, time-consuming procedure. Therefore, although the SDS-PAGE zymography is sensitive enough and relatively inexpensive, in some circumstances the better choice for a fast MMP assessment could be the fluorescent zymography.
\n\t\t\t\tThe fluorescent zymography is based on a technology known as the fluorescence resonance energy transfer (FRET). Briefly, the tested sample is incubated in small volume (10-20 μl) of reaction mixture containing the substrate, that is labeled with fluorochrome and quencher tags. When a substrate remains intact, the energy emitted by fluorochrome is entirely absorbed by the quencher, therefore no fluorescence is detected. The substrate degradation abolishes the suppressive effect of the quencher on fluorochrome, thus resulting in increase of fluorescence in the reaction mixture. The intensity of fluorescence corresponds to the amount of digested substrate, that, in turn, reflects the amount of active enzyme in a sample (Fig. 3B).
\n\t\t\t\t\tSchematic representation of main methods of MMPs detection (description in text).
Oppositely to standard SDS-PAGE zymography, this method is very fast and enables the measurement of proteolytic activity in analyzed samples within several minutes. In contrast to the previously mentioned ELISA and SDS-PAGE zymography, the fluorescent zymography allows an assessment of the direct influence of various factors on MMP activity. However, the outcome of the analysis is highly sensitive to sample preparation and the reaction conditions. The samples should be prepared without addition of EDTA or other metal-ion chelators, and without addition of protease inhibitors. This step may be of great importance for final results of analysis, especially since the extraction procedures themselves may induce MMPs activation or lead to release of natural MMP inhibitors. After tissue disruption during sample preparation, these inhibitors, although initially localized in different compartments, can interact with active enzymes, and thus, may affect the results of assay. Another important issue may be the concentration of non-ionic detergents in the reaction mixture, which may “neutralize” small molecules that potentially could interfere with MMP activity (Kupai et al., 2010).
\n\t\t\t\t\tThe most significant disadvantage of the fluorescent zymography is, that it does not determine MMP, that directly contributes to the observed substrate degradation. This obstacle may be omitted by the use of respective, MMP-specific, monoclonal antibodies, which block the proteolytic activity of the selected enzyme. With a panel of blocking antibodies, this modification allows the quantitative assessment of each constituent of MMP-mediated proteolytic activity in the analyzed sample.
\n\t\t\t\t\tAnother solution to this problem may be the method that combines the idea of both, ELISA and fluorescent zymography. Briefly, the plate is coated with specific anti-MMP antibodies, which capture molecules of the respective enzyme from the sample being assessed. Then, non-captured, unspecific proteins are washed out and the fluorochrome/quencher-labeled substrate is added to the plate followed by incubation. Finally, since the intensity of MMP-mediated fluorescence corresponds to the activity of specific MMP, it may be measured using the fluorescence plate reader. This solid-phase, or immunocapture fluorescent zymography represents the key advantages of both, ELISA and “normal” fluorescent zymography (Fig. 3C). It enables a measurement of enzymatic activity of individual MMPs, is specific, sensitive, rapid and lacks the previously mentioned main deficiencies of both methods.
\n\t\t\t\tIn studies concerning distribution of MMPs in affected tissues, the use of
The main disadvantage of this method is that it does not allow precise measurement of the amount of active MMP. Moreover, similarly to “normal” fluorescent zymography, it is necessary to use neutralizing antibodies, to determine MMPs that contribute to substrate cleavage.
\n\t\t\t\tThe studies concerning the role of MMP in pathogenesis of aortic aneurysm include also a method that enables assessment of the natural tissue inhibitors of MMP (TIMPs). This method, known as reverse zymography, utilizes polyacrylamide gel with specific substrate, that is additionally supplemented with respective MMP. After electrophoresis of tested samples the gel is subjected to the same processing as in routine zymography. Then, the MMP, which is equally distributed in the whole gel, cleaves the substrate with the exception of those places, where TIMPs inhibit its proteolytic activity. Those places are visible as Coomassie blue-stained bands, whereas the other parts of the gel remain unstained.
\n\t\t\t\tIn addition to reverse zymography, the expected interaction between MMPs and their tissue inhibitors can also be analyzed using a modified western blotting (SDS-PAGE and immunoblotting) method. The formation of higher molecular weight complex by interacting molecules results in its slower migration during polyacrylamide gel electrophoresis, and thus reveals a band shift of specific MMP or its inhibitor, depending on the antibody used for detection.
\n\t\t\t\tCurrently, the methods of MMPs analysis in aortic aneurysm clinics described above are predominantly used for research purpose. However, due to an increasing interest in the monitoring of MMPs level and/or activity in aneurysm-suffering patients, it is plausible that some of these methods will become the standard diagnostic tools in the near future.
\n\t\t\t\t\tThe first postulated indication for clinical use could be the screening of plasma MMPs activity in patients with newly recognized aortic aneurysm. Although there is no consent, whether low plasma levels of MMPs may be considered as a low risk indicator of aneurysm progression and/or rupture, it is nevertheless widely accepted that the higher concentration, or more precisely, their higher activity should at least encourage more frequent monitoring of aneurysm diameter. The second, important clinical application for MMP assessment seems to be the periodic monitoring of MMPs activity in patients with small aneurysms and subjected to pharmacological treatment. Obviously, the method selected for monitoring should depend on the mechanism of action of controlled MMP modulator. Thus, the monitoring of pharmacological treatment of aortic aneurysm using compounds displaying indirect influence on MMP amount and/or activity, including statins, heparins or ODNs, may engage a broad spectrum of methods mentioned above. However, in regimens using potent direct MMP inhibitors, e.g. tetracycline-derivatives, or angiotensin converting enzyme-inhibitors, the fluorescent zymography rather, than other methods, including substrate-specific SDS-PAGE zymography, should be used preferentially.
\n\t\t\t\t\tIt has been found that open aneurysm repair leads to transient (usually within first 3 moths) MMP-9 increase, followed by its later significant reduction. Nevertheless, in some patients high levels of MMPs may still persist even a very long time after surgery (Kadoglou & Liapis, 2004). An interesting example of this condition may by the case of a 50-year old men with an abdominal aortic aneurysm, subjected to successful open aneurysm repair. Surprisingly, after 4 years the patient was qualified again for surgical treatment due to the significant enlargement of the thoracic aorta, remaining suprarenal part of abdominal aorta and common iliac arteries. The plasma level of MMP-2 was similar to those observed in other aortic aneurysm-suffering individuals. However, his MMP-9 plasma activity was extraordinarily (almost 10-fold) higher, than mean MMP-9 level, observed in other patients bearing an aortic aneurysm.
\n\t\t\t\t\tIn contrast to open repair, patients subjected to endovascular aneurysm exclusion usually reveal a gradual decrease of circulating MMP-3 and -9, whereas the persisting high concentration and/or activity of circulating MMP-9 actually correlates with some postoperative complications. They include graft migration, or presence of endo-leak, where both conditions are accompanied by the contact of circulating blood with the thrombus still existing in the aneurysm lumen (Kadoglou & Liapis, 2004). Therefore, the temporary monitoring of MMP activity may be an important diagnostic procedure also in patients after both, open surgical, but also endovascular intervention.
\n\t\t\t\tDespite numerous studies, the role of MMPs in pathogenesis of aortic aneurysm remains unclear. Also, the question, whether they are “executors”, or “executioners”, is still unanswered. Since MMPs are obviously engaged in all stages of the aneurysm development, from the beginning, till the fatal aneurysm rupture, they are very attractive targets in approaches, concerning pharmacological treatment of this pathology. However, due to some discrepancies between results of experimental, as well as clinical studies conducted so far, this issue still requires intensive research. Nevertheless, it is plausible that in the near future the majority of patients with aortic aneurysms might simply require regular drug intake, without the necessity for surgical intervention, which would be reserved for particular cases only. Since it is very similar to the history of management of gastric ulcers, this vision seems to be quite realistic in the near future…
\n\t\tTo perform their vital functions, anterior pituitary cells must respond appropriately to their unique hypothalamic releasing hormones, while also responding to extrinsic signals informing them of the body’s nutritional and metabolic state. Leptin is one of the most important of these extrinsic signals. However, recent studies show that leptin does more than simply signal levels of fat stores [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11]. Leptin plays a trophic role that optimizes and maintains differentiation of at least two of these cell types, somatotropes and gonadotropes.
Anterior pituitary somatotropes produce growth hormone (GH) to support growth in muscles and bones before puberty and build muscle, bone, and reduce fat to optimize body composition in the adult [12, 13]. Gonadotropes produce the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), which differentially regulate gonadal functions, ovulation and reproductive cyclicity [14]. Both somatotrope and gonadotrope functions are impacted by the nutritional state and therefore it is not surprising that they exhibit a dependency on leptin. Early studies showed significant reductions in numbers of gonadotropes in leptin-deficient animals [6, 15, 16, 17, 18, 19]. Similarly, rodents that lack leptin or leptin receptors (LEPR) had reduced numbers of somatotropes [20, 21]. Our studies on the distribution of pituitary LEPR showed expression in nearly all cells [1, 22].
A dependency on normal levels of serum leptin was seen in our studies of 24 h fasted rats, when we correlated the reduction in serum leptin with reduced numbers of immunolabeled somatotropes and gonadotropes, along with reduced receptivity for gonadotropin releasing hormone (GnRH) and growth hormone releasing hormone (GHRH) [23]. As these findings pointed to potential trophic actions by leptin, we continued
These findings agree with recent
Leptin’s restorative or stimulatory effects directly on somatotropes and gonadotropes have since led to studies that explored the significance of this regulatory influence as well as basic mechanisms of action, including the identification of signaling pathways and transcription factors. This chapter will review the studies which have identified critical leptin target molecules that are vital to the differentiated function of gonadotropes and somatotropes. We will also review signaling pathways used by leptin to stimulate production of these targets. Finally, we will show how leptin may contribute to plasticity of the pituitary by supporting multihormonal cell populations.
The overall importance of leptin to reproduction was established soon after its discovery [5]. Leptin alone will restore fertility in leptin-deficient animals and humans [4, 15, 16, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36]. There are distinct sex differences in serum leptin levels in the adult. After puberty, adult males have relatively low leptin levels, when compared with females [37, 38, 39, 40, 41]. This sex difference may reflect the differential regulation of leptin by gonadal steroids. Androgens inhibit leptin secretion to prevent leptin inhibition of testicular function (reviewed in [5]). In females by contrast, estrogens stimulate leptin secretion. The rise in estrogen early in the cycle may contribute to the 2-3-fold increase in leptin levels known as the midcycle leptin surge [37, 39].
With respect to gonadotrope function, studies have also reported a synchrony between nocturnal leptin and LH pulses in normal cycling women [36, 37]. Indeed, a comprehensive study of 259 cycling women reported that the highest levels of leptin were correlated with the timing of the LH surge [37]. In contrast, anovulatory cycles were associated with overall low leptin levels.
Shortly after leptin was discovered, pioneering studies by Yu et al. [10] demonstrated that leptin stimulated LH and FSH release,
Our studies on the importance of leptin to gonadotropes began with the detection of leptin receptors (LEPR) in dispersed pituitary cells from male and cycling female rats and mice [1]. The expression of LEPR varied with the stage of the cycle and was seen in 40-50% of anterior pituitary cells from males and females in metestrus or diestrus. LEPR expression increased to 60-80% of AP cells in proestrous and estrous females, which coincided with the midcycle rise in serum leptin [1].
To determine if the increase reflected changes in gonadotrope receptivity, dual labeling was performed for LEPR and gonadotropins. The results showed that 90% of gonadotropes identified by the stores of luteinizing hormone (LH) or follicle stimulating hormone (FSH) expressed LEPR in males and throughout all stages of the cycle in females [1]. Some of the increase in LEPR in proestrous females was due to an increase in cells expressing LH and LEPR, which occurs just before the LH surge.
The findings showing an overall increase in LEPR early in the estrous cycle stimulated studies to determine potential regulators for this expression. We treated one day cultures of anterior pituitary cells from diestrous female mice with estradiol overnight and then treated a subset of these cultures with 10 or 100 pg./ml neuropeptide Y (NPY) for 3 h. Figure 1 shows that estradiol or NPY alone (100 pg./ml) stimulated a significant 2--fold increase in LEPR-bearing cells and that the effects of the two were not additive. In contrast, NPY did not stimulate LEPR expression in anterior pituitary cells from male mice (data not shown). Collectively, these data support the hypothesis that rising estradiol early in the cycle may stimulate an increase in pituitary receptivity to leptin which may serve as a gateway for leptin’s permissive actions [7].
Estradiol and NPY stimulate LEPR expression in 1-day cultures of anterior pituitary cells. * = significantly higher values than all other values; ANOVA + Bonferroni’s post hoc test. Note: These are original data, not published elsewhere.
Having established the presence of the receptor population in gonadotropes, we determined if leptin acted on gonadotropes through the Janus Kinase-Signal Transducer and Activator of Transcription (JAK–STAT) pathway. Following leptin stimulation for 10-60 min
The next series of studies investigated leptin’s importance to gonadotrope function by selectively ablating LEPR in gonadotropes with Cre-LoxP technology. This work fills a critical knowledge gap, because, as summarized in our recent review [5], much of the research surrounding leptin’s role in reproduction has been focused in the hypothalamus. There was a growing body of evidence showing that leptin’s regulatory actions were mediated through its stimulation of Kisspeptin neuronal pathways that regulate GnRH neurons (reviewed in [5]).
Our first set of studies used Cre-recombinase driven by the
The first question to be addressed related to the impact of loss of LEPR in gonadotropes on pubertal development, growth, and fertility of the mice [1]. When LEPR exon 17 was deleted in gonadotropes with the Cre-
We analyzed hormone levels in mice lacking LEPR exon 17 and reported that loss of LEPR resulted in several deficits [1]. In mutant diestrous females, serum levels of LH, FSH, and GH were reduced. In contrast, mutant males showed reductions in GH, prolactin (Prl), and thyroid stimulating hormone (TSH), but no reductions in gonadotropins. The loss of LEPR resulted in reduced
However, during this phase of the study, we detected Cre-recombinase in the testes and therefore continued these studies focusing only on mutant females [7] bearing Cre-
We were able to study cyclicity in the progeny from the two F3 fertile females. These mutant F4 female progeny cycled irregularly. Two of them remained in diestrus and the remaining females spent more time in diestrus than normal females. Collectively, these breeding studies showed that ablation of all isoforms of LEPR in gonadotropes had a profound impact on a subset of females; less than half could cycle and were fertile [7]. This highlighted the importance of leptin to gonadotrope functions. However, because of the infertility issues in the line expressing Cre-LH X LEPR exon 1, our ongoing studies have now switched to mice bearing Cre-recombinase driven by the
After we characterized the deletion mutants lacking LEPR in gonadotropes, we hypothesized that rising leptin early in the cycle may have a permissive effect on the rise in pituitary GnRHR levels [7], which could serve as a gateway that permitted full receptivity to GnRH and facilitates the LH surge. We treated pituitary cells from normal diestrous female mice with 10 nM leptin and showed a significant increase in GnRHR proteins [7]. We also detected leptin-stimulated increases in pituitary activin (but not inhibin) mRNA (
We have demonstrated that expression of
Another link between leptin and FSH was reported by studies that restored LEPR in gonadotropes from mice that were genetically engineered to be globally deficient in LEPR [49]. As expected, fertility was not restored, because the mice were morbidly obese, and kisspeptin and GnRH neuronal function was still deficient. However, they did report elevated FSH levels in these mice. It was not determined whether restoration of the leptin signal influenced GnRHR expression.
The reduced
Figure 2 illustrates how the ovary and adipocytes may partner in the remodeling of gonadotropes to support the development of the follicles with key cellular regulatory pathways and outputs indicated. This cartoon focuses mainly on leptin, FSH and estrogen. We propose that normal levels of leptin permit a rise in FSH early in the cycle regulating FSH directly or through activin. This could be an important checkpoint if leptin levels drop due to fasting, for example [23] as this may signal poor nutrition and reduce FSH production. The cartoon then shows that FSH stimulates ovarian follicles to produce and secrete estrogen, which stimulates a rise in serum leptin. The growth in ovarian follicles and subsequent rise in estrogen also has positive feedback actions on GnRH neurons (shown in ref. [5]) and the gonadotropes. Estrogen may also stimulate a rise in pituitary LEPR (Figure 1), which renders the gonadotropes more responsive to leptin.
Gonadotropes are remodeled early in the cycle by estrogens, GnRH, and leptin to support the ovary. We postulate that normal levels of leptin permit FSH release directly or through activin. FSH stimulates the growing population of follicles, which produce more estrogen. This rise in estrogen may stimulate leptin release from adipocytes and the expression of LEPR in gonadotropes. Estrogen also exerts positive feedback on the neuronal circuit that regulates GnRH, which produce more rapid GnRH pulses, which also stimulate
Not shown in this cartoon is GnRH, which is secreted in response to estradiol positive feedback to stimulate gonadotrope production of gonadotropins and GnRHR (pathway shown in ref. [5]). GnRH and estradiol both stimulate
Figure 2 also shows the pathway that regulates the third target for leptin, GnRHR. This receptor appears to be regulated post-transcriptionally by leptin, because
Our studies of leptin stimulation of GnRHR proteins showed a dose response relationship between leptin and expression of GnRHR (detected by enzyme assays) or Biotinylated GnRH binding to living pituitary cells (detected cytochemically) [8] After we confirmed that leptin stimulated GnRHR proteins, but not mRNA, we determined by electrophoretic mobility shift assays that Musashi1 interacted directly with the
To summarize, our studies of leptin actions on gonadotropes have shown severe functional deficiencies in gonadotropes lacking exon 1 of LEPR. The total absence of the LEPR caused infertility in a subset of females [7]. Collectively, studies of these animal models point to key gene products that are affected by loss of leptin signals. Leptin may be important in the transcription of
The loss of leptin receptors in gonadotropes also had a broader impact on pituitary function. We reported a profound reduction in serum GH, in both mutant males and females (Figure 3) [1]. This reduction would expect to result in growth hormone deficiency, which, in our other models has resulted in significant changes in body weight (adult-onset obesity) [22]. However, when mice were weighed regularly for nearly a year, these deletion mutant animals grew normally and did not gain more weight than normal mice during their first year of life [1]. In addition, male mutants show reduced levels of serum TSH and prolactin [1]. There were also sex-specific differences in mRNA levels. As stated earlier, in deletion mutant females,
Mutants lacking Lepr exon 17 in gonadotropes show significantly reduced levels of serum GH. This colored figure has not been published elsewhere. However, the data were published as separate figures (separating sexes) in ref. [
The presence of multihormonal gonadotropes in the rodent pituitary cell population is not unexpected since our group previously reported cells that stored gonadotropins and either ACTH [54, 55, 56] or GH [57, 58]. Early studies of gonadotropes purified by centrifugal elutriation reported a fraction that contained 91-93% immunolabeled LH-FSH cells (a 9-fold enrichment). This group of cells were enriched based on their response to GnRH. The stimulated secretion caused them to enlarge. Which allowed them to be separated and enriched in a fraction containing larger cells. The fraction also contained gonadotropes that immunolabeled for other hormones. In the female gonadotrope fraction, we detected: 29.2% GH cells, 4% prolactin cells, 6.8% adrenocorticotropin (ACTH) cells, and 2.8% thyroid stimulating hormone cells (TSH [59]).
More recently we bred a Cre-reporter gene into our Cre-LH line to purify gonadotropes by fluorescence activated cell sorting mice [60]. Floxed tdTomato (red fluorescence) was expressed in all pituitary cells. However, in cells bearing Cre-recombinase (Cre-Lhb), the tdTomato was ablated promoting the expression of eGFP (green fluorescence). Thus, all non-gonadotropes (not producing Cre-
Figure 4 shows the FACS separation profiles for non-fluorescent pituitary cells (Figure 4A); fluorescent Cre-negative populations bearing only tdTomato (Figure 4B) and Cre-positive populations, which contain the eGFP cells (Figure 4C). Assays for content of gonadotropins and GnRH receptors show that over 95% of the total content is in the eGFP fraction (Figure 4D–F). Over 90% of eGFP cells were immunolabeled for LH (Figure 4G). However, multihormonal expression is evident as shown in Figure 4H–K. The eGFP fraction contains 30% of the GH and TSH content and 10% of the ACTH and prolactin content. In contrast, the non-gonadotrope, tdTomato fraction (red bars) contain over 70% of the content of GH and TSH and 90% of the content of ACTH and prolactin.
FACS experiment comparing non-fluorescent cells (4A) with those bearing tdTomato-eGFP, but no Cre-recombinase (4B) and those bearing Cre-recombinase, which ablates the tdTomato, allowing expression of eGFP (4C). Only the profile in 4C shows the presence of eGFP cells. (D–F) show that >90% of LH, FSH, and GnRHR is assayed in the eGFP fraction and barely detectable in the tdTomato fraction. Immunolabeling in (G) shows that >90% of the eGFP cells are labeled for LH (cyan shows blue label over eGFP green). (H–K) detect 70-90% of other pituitary hormones in the tdTomato fraction, but 10-30% of these hormones are found in the pure gonadotrope fraction. These data have never been published elsewhere and are original to this chapter.
When mRNA levels were assayed by qPCR, similar results were seen. Figure 5A shows the 72-88% enrichment in gonadotropin and
(A) qPCR assays show enrichment in Lhb, Fshb, and Gnrhr mRNA in eGFP fraction. These data have not been published elsewhere and are original. (B) Shows enrichment of Gh, Prl, and Pit1 mRNA levels in tdTomato fractions, but expression of about 20% of the total in the gonadotrope fraction. (C) Shows Tshb and Pomc mRNA levels and about 20% are in the gonadotrope fraction and 80% in the tdTomato fraction. These data have not been published elsewhere and are original to this chapter.
FACS fractions from male mice from this line were also analyzed for mRNA content and similar enrichment of gonadotropins and
More recently, multihormonal pituitary cell populations have been detected by single cell RNA-sequencing, especially in the study by Ho et al. [61], which investigated changes in multihormonal cell transcriptome patterns in mice subjected to different physiological stresses. As we have outlined in a recent review [62], these pools of multihormonal cells may serve to support pituitary plasticity and add to the functions of pituitary populations as physiological needs arise. We hypothesize that these cells may include progenitor cells. Our data showing that gonadotrope LEPR-null mice have deficiencies in other hormones suggest that leptin may regulate multihormonal expression from this group of cells. The fact that secretion of a particular hormone is reduced in animals with LEPR-null gonadotropes highlights the importance of leptin to multihormonal function and suggests a role for leptin in the regulation of pituitary plasticity.
Somatotropes are vital metabolic sensors because they directly regulate stores of fat as they build muscle, bone, and regulate optimal body composition [63]. Most somatotropes bear leptin receptors [64, 65] and leptin deficiency results in reduced somatotrope functions [4, 20, 66, 67, 68]. As stated in the introduction, leptin treatment of leptin deficient
Our studies of leptin’s regulation of somatotropes began with the ablation of LEPR exon 17 or exon 1 with Cre-recombinase driven by the rat GH promoter [22, 69]. Both models showed GH deficiency, adult-onset obesity and metabolic dysfunction. At the level of the pituitary, this deficiency was seen as a reduction in GH and GHRHR.
We also reported sex-specific deficiencies during postnatal development with the discovery that leptin may target two transcription factors important in the production of GH, GHRHR, PRL, and TSH. These included Prophet of Pit1 (Prop1) and Pou1f1 [70]. Ablation of LEPR exon 1 in somatotropes reduced Pou1f1 in neonatal females along with serum prolactin. GH stores detected by immunolabeling were also reduced in both neonatal males and females. Interestingly, the lack of LEPR promoted an increase in Prop1 in neonatal males.
The studies of the impact of loss of LEPR were continued on FACS purified somatotropes [60]. Purified somatotropes showed reductions in GH, as expected, however they also contained a subset of multihormonal cells storing TSH and/or prolactin. In somatotrope LEPR-null females, TSH and prolactin stores were reduced in the pure somatotrope fraction [60]. Taken together, our analysis of somatotropes that lack LEPR shows that this multihormonal subset is significantly reduced, suggesting once more that leptin may play a role in maintaining multihormonal expression and promoting pituitary cell plasticity. Finally, these studies also demonstrated that Pou1f1 was reduced in pure somatotropes, which may explain the reduction in any or all hormones dependent on this transcription factor (GH, GHRHR, TSH and prolactin) [60].
We continued the investigation of leptin signaling pathways in somatotropes and reported that they included both transcriptional and posttranscriptional regulators [3]. Our tests of pathway inhibitors showed that full GH expression may be maintained by leptin through the JAK/STAT3 pathway but not nitric oxide. This contrasts with leptin pathways that regulate gonadotropins, which include NOS. Leptin regulation is likely to be transcriptional as loss of LEPR in somatotropes reduced
However, regulation of POU1F1 by leptin appears to be via post-transcriptional mechanisms as loss of LEPR in somatotropes causes reduction in mRNA levels of the Pou1f1 protein, but not the
An
Our studies of animal models in which LEPR was ablated in gonadotropes or somatotropes opened the door to the discovery that leptin may regulate some of its target gene products by post-transcriptional pathways. The post-transcriptional targets included
The concept that Musashi would be involved in the translational regulation of either
Since our findings indicated that Musashi was involved in the repression of translation of
Our studies also showed that leptin may directly reduce expression of Musashi in its target cells. In pituitaries from proestrous female mice lacking LEPR in gonadotropes,
Similarly, Musashi1 protein and
Our
Pituitary gonadotropes and somatotropes were initially shown to be most vulnerable to the global loss in leptin signals as demonstrated by their reduction in numbers in the population, even following acute fasting. As little as 10-100 pg./ml leptin directly restored hormone levels in these populations, so they could once more be detected by immunolabeling. We now have much more information about the impact of loss of leptin signaling to model animals including infertility when they carried LEPR-null gonadotropes and adult-onset obesity and GH deficiency when they carried LEPR-null somatotropes. We have identified specific leptin targets in each of these cell types and determined that leptin regulation may involve both transcriptional and post-transcriptional pathways. The target molecules are vital to the differentiated function of these cells, which highlights a role for leptin in maintaining their differentiated state. Regarding post-transcriptional pathways, we have shown that leptin also regulates expression of the translational regulatory protein, Musashi. Our studies have led to the discovery of novel roles for Musashi, implicating this regulator in the repression of targets in specific pituitary cell types. This broadens the scope of Musashi’s regulatory role beyond that of regulation of stem cells. Finally, our studies of purified somatotropes and gonadotropes have confirmed the presence of multihormonal expression in a subpopulation of cells and have led to the discovery that leptin signaling is needed to maintain this subset. The presence of these multihormonal pituitary cells is also evident in single cell RNA-sequencing studies. Future studies are needed that focus on the role leptin plays in maintaining this cell population, which supports pituitary plasticity. Future investigation will elucidate the role Musashi may play in the selective regulation of specific hormones or their transcription factors.
The authors are grateful for the outstanding technical assistance of Anessa Haney, Linda Hardy, and Alex Lagasse. The authors acknowledge funding from the following sources; National Institute of Health (NIH) R01 HD059056 (GVC); NIH R01 HD-087057 (GVC, AMM); NIH R01 HD-093461 (AMM, GVC, and MCM); NIH R01 DK113776 (GVC, AMM, and MCM); and NIH R01 DK 127723 (GVC, AMM, and MCM). We also acknowledge pilot studies grants from the Sturgis Foundation (AMM, GVC) and Development Enhancement Awards (GVC, AO) from UAMS. We also acknowledge support for core facilities from Center grants- NIGMS P20 GM103425 and P30 GM11070 (Dr. Edgar Garcia-Rill PI).
The authors declare no conflict of interest.
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More specifically, I explored the consequences of the dynamics detected by the models on monetary policy implementation for 10 OECD countries. This study indicates that factors that may cause a rise in short-term interest rates with respect to the USA can lead to volatility in exchange rates and thus macroeconomic instability. It is also implied that sustaining macroeconomic growth and decreasing inflation can result in increased export performance, which in turn provides the amount of US dollars to curb volatility in US dollar quotations. Accordingly, this study reveals that high importance should be given to both monetary and non-monetary factors in the open-economy framework to detect the possible impacts on trade and capital flows by dynamic stochastic general equilibrium (DSGE) models. Due to their exchange rate risk of economic agents, I also suggest that the economic policy makers of these countries had better create a theoretical framework including financial frictions, economic agents’ preferences and different shocks to smooth the variations in exchange rates and minimise the negative outcomes of Brexit.",book:{id:"6487",slug:"trade-and-global-market",title:"Trade and Global Market",fullTitle:"Trade and Global Market"},signatures:"Oguzhan Ozcelebi",authors:[{id:"226325",title:"Prof.",name:"Oguzhan",middleName:null,surname:"Ozcelebi",slug:"oguzhan-ozcelebi",fullName:"Oguzhan Ozcelebi"}]},{id:"53827",title:"Malaysia and China: The Trade Balances, Foreign Exchanges and Crises Impacts",slug:"malaysia-and-china-the-trade-balances-foreign-exchanges-and-crises-impacts",totalDownloads:2106,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"China appears as the biggest trading partner for ASEAN economies, but it is inconclusive whether the complementarities between China and regional economies offset China’s competitive threat. This study tries to assess if real exchange fluctuations and the demand-supply channels determine the Malaysia-China trade balances in the global crises era, 1997–2010. The finding generally supports the complementary role of China in the Malaysia-China bilateral trading. However, despite the long-run effect of real exchange on trade balances, the Keynesian demand channel was not uphold during and after the global financial crisis—due to the contractionary effect on Malaysian output. The Chinese inflation impact is also not evident following the foreign exchange shocks. Meanwhile, currency devaluation for exports gains is insufficient to sustain Malaysia output expansion against China. 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Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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