Physiological parameters of cardiac and myofiber function in Tpm mouse models.
\\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!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 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 252 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!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"3829",leadTitle:null,fullTitle:"Antioxidant-Antidiabetic Agents and Human Health",title:"Antioxidant-Antidiabetic Agents and Human Health",subtitle:null,reviewType:"peer-reviewed",abstract:"The human system employs the use of endogenous enzymatic as well as non-enzymatic antioxidant defence systems against the onslaught of free radicals and oxidative stress. Enzymatic antioxidants and non-enzymatic antioxidants work synergistically with each other, using different mechanisms against different free radicals and stages of oxidative stress. Dietary and lifestyle modifications are seen as the mainstay of treatment and management of chronic diseases such as diabetes mellitus. The major aims of dietary and lifestyle changes are to reduce weight, improve glycaemic control and reduce the risk of coronary heart disease, which accounts for 70- 80% of deaths among those with diabetes. It is also important to note that medicinal plants have been used as medicines since ancient time, and continue to play significant role even in modern medicine in management and treatment of chronic diseases. Impressive numbers of modern therapeutic agents have been developed from plants. Phytochemicals have been isolated and characterised from fruits such as grapes and apples, vegetables such as broccoli and onion, spices such as turmeric, beverages such as green tea and red wine, as well as many other sources. The WHO estimates that approximately 80% of the worlds inhabitants rely on traditional medicine for their primary health care and many medicinal plants have ethno-medical claims of usefulness in the treatment of diabetes and other chronic diseases globally, and have been employed empirically in antidiabetic, antihyperlipidemic, antihypertensive, antinflammatory and antiparasitic remedies. This book examines the role of antioxidant-rich natural products in management and treatment of diabetes and other chronic diseases.",isbn:null,printIsbn:"978-953-51-1215-0",pdfIsbn:"978-953-51-7190-4",doi:"10.5772/57029",price:139,priceEur:155,priceUsd:179,slug:"antioxidant-antidiabetic-agents-and-human-health",numberOfPages:382,isOpenForSubmission:!1,isInWos:1,hash:"148f7976e4249aa1f0180cca370e36ce",bookSignature:"Oluwafemi Oguntibeju",publishedDate:"February 5th 2014",coverURL:"https://cdn.intechopen.com/books/images_new/3829.jpg",numberOfDownloads:45676,numberOfWosCitations:61,numberOfCrossrefCitations:16,numberOfDimensionsCitations:69,hasAltmetrics:1,numberOfTotalCitations:146,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 26th 2013",dateEndSecondStepPublish:"May 17th 2013",dateEndThirdStepPublish:"August 21st 2013",dateEndFourthStepPublish:"November 19th 2013",dateEndFifthStepPublish:"March 24th 2014",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"32112",title:"Prof.",name:"Oluwafemi",middleName:"Omoniyi",surname:"Oguntibeju",slug:"oluwafemi-oguntibeju",fullName:"Oluwafemi Oguntibeju",profilePictureURL:"https://mts.intechopen.com/storage/users/32112/images/3371_n.jpg",biography:"Prof Oluwafemi.O Oguntibeju is an Associate Professor and Group Leader (Nutrition and Chronic Disease Research Unit) at the Oxidative Stress Research Centre in the Department of Biomedical Sciences, Faculty of Health & Wellness, Cape Peninsula University of Technology Bellville, South Africa. He lectures and supervises postgraduate students and collaborates with national and international scientists. Over the years, he has been involved in the field of nutrition and HIV/AIDS and related-public health issues but more recently on diabetes. He has published over 90 scientific papers in peer-reviewed journals, presented over 30 papers at national and international conferences and reviewed manuscripts for over 30 international scientific journals. He has received various awards such as the Gold Research Excellence Award at his current university. Prof O.O Oguntibeju is a National Research Foundation (NRF) C-rated researcher and holds a master degree in Biochemistry from the University of Ibadan, Nigeria and a doctoral degree in Biomedical Science at the Central University of Technology, Bloemfontein, South Africa. He is a Chartered Scientist (CSci, UK) and Fellow of the Institute of Biomedical Science, London. He enjoys reading and music and he is married to Faustina and has four children.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"3",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1013",title:"Pediatric Endocrinology",slug:"pediatric-endocrinology"}],chapters:[{id:"45944",title:"Lipid Profile, Antidiabetic and Antioxidant Activity of Acacia ataxacantha Bark Extract in Streptozotocin-Induced Diabetic Rats",doi:"10.5772/57151",slug:"lipid-profile-antidiabetic-and-antioxidant-activity-of-acacia-ataxacantha-bark-extract-in-streptozot",totalDownloads:2529,totalCrossrefCites:0,totalDimensionsCites:4,signatures:"Rotimi O. Arise, Aderounmu I. 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\r\n\tThe study of populations and plant communities in their different aspects; ecological, structural, functional and dynamic, it is essential to establish a posteriori models of forest and agricultural management.
\r\n\tFor this, the methodological approaches on the type of sampling are considered essential, since there are differences between the purely ecological and the phytosociological methods, despite the fact that both pursue the same objective.
\r\n\tAlthough the ecological method for the knowledge of the vegetation is widely extended, the phytosociological one is no less so, since in the European Union it has been developed as a consequence of policies on sustainability, through which regulations have been issued, such as the habitats directive.
\r\n\tOn the other hand, research on plant dynamics and knowledge of the landscape in an integral way, have multiplied in the last 30 years, which has favored a deep knowledge of the floristic and phytocenotic wealth, which is fundamental for agricultural management, livestock and forestry.
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Carrillo-Casas, Rigoberto Hernández Castro",authors:[{id:"74267",title:"Dr.",name:"Rigoberto",middleName:null,surname:"Hernández-Castro",fullName:"Rigoberto Hernández-Castro",slug:"rigoberto-hernandez-castro"},{id:"80534",title:"MSc",name:"Lucia Del Carmen",middleName:null,surname:"Favila-Humara",fullName:"Lucia Del Carmen Favila-Humara",slug:"lucia-del-carmen-favila-humara"},{id:"80562",title:"Prof.",name:"Gilberto",middleName:null,surname:"Chávez-Gris",fullName:"Gilberto Chávez-Gris",slug:"gilberto-chavez-gris"},{id:"80579",title:"MSc.",name:"Francisco J",middleName:null,surname:"Garcia-Vázquez",fullName:"Francisco J Garcia-Vázquez",slug:"francisco-j-garcia-vazquez"},{id:"80580",title:"Dr.",name:"José María",middleName:null,surname:"Remes-Troche",fullName:"José María Remes-Troche",slug:"jose-maria-remes-troche"},{id:"80581",title:"Dr.",name:"Luis F",middleName:null,surname:"Uscanga",fullName:"Luis F Uscanga",slug:"luis-f-uscanga"},{id:"80583",title:"Dr.",name:"Marco A",middleName:null,surname:"Santillán-Flores",fullName:"Marco A Santillán-Flores",slug:"marco-a-santillan-flores"},{id:"80584",title:"Dr.",name:"Fernando",middleName:null,surname:"Paolicchi",fullName:"Fernando Paolicchi",slug:"fernando-paolicchi"},{id:"83061",title:"MSc.",name:"Erika Margarita",middleName:null,surname:"Carrillo-Casas",fullName:"Erika Margarita Carrillo-Casas",slug:"erika-margarita-carrillo-casas"}]},{id:"26009",title:"Mycobacterium avium ssp. paratuberculosis vs Crohn’s Disease",slug:"mycobacterium-avium-ssp-paratuberculosis-vs-crohn-s-disease",signatures:"Isabel Azevedo Carvalho, Maria de Lourdes de Abreu Ferrari and Maria Aparecida Scatamburlo Moreira",authors:[{id:"79631",title:"Prof.",name:"Maria Aparecida Scatamburlo",middleName:null,surname:"Moreira",fullName:"Maria Aparecida Scatamburlo Moreira",slug:"maria-aparecida-scatamburlo-moreira"},{id:"81197",title:"Ms.",name:"Isabel",middleName:"Azevedo",surname:"Azevedo Carvalho",fullName:"Isabel Azevedo Carvalho",slug:"isabel-azevedo-carvalho"},{id:"81200",title:"Prof.",name:"Maria De Lourdes de Abreu",middleName:null,surname:"Ferrari",fullName:"Maria De Lourdes de Abreu Ferrari",slug:"maria-de-lourdes-de-abreu-ferrari"}]},{id:"26010",title:"Manipulation of Intestinal Flora as a Way to Treat Crohn's Disease: The Role of Probiotics, Prebiotics and Antibiotics",slug:"manipulation-of-intestinal-flora-as-a-way-to-treat-crohn-s-disease-the-role-of-probiotics-prebiotics",signatures:"Petra Zadravec, Borut Štrukelj and Aleš Berlec",authors:[{id:"71597",title:"Dr.",name:"Ales",middleName:null,surname:"Berlec",fullName:"Ales Berlec",slug:"ales-berlec"},{id:"109429",title:"Prof.",name:"Borut",middleName:null,surname:"Štrukelj",fullName:"Borut Štrukelj",slug:"borut-strukelj"},{id:"112590",title:"MSc.",name:"Petra",middleName:null,surname:"Zadravec",fullName:"Petra Zadravec",slug:"petra-zadravec"}]},{id:"26011",title:"Evidence-Based Evaluation of Biological Treatment in Crohn's Disease",slug:"evidence-based-evaluation-of-biological-treatment-in-crohn-s-disease",signatures:"Shiyao Chen and Yuan Zhao",authors:[{id:"71924",title:"Prof.",name:"Shiyao",middleName:null,surname:"Chen",fullName:"Shiyao Chen",slug:"shiyao-chen"},{id:"120590",title:"Dr.",name:"Yuan",middleName:null,surname:"Zhao",fullName:"Yuan Zhao",slug:"yuan-zhao"}]},{id:"26012",title:"Minimally Invasive Surgical Treatment in Crohn’s Disease",slug:"minimally-invasive-surgical-treatment-in-crohn-s-disease",signatures:"Antonino Spinelli, Piero Bazzi, Matteo Sacchi and Marco Montorsi",authors:[{id:"70711",title:"Dr.",name:"Antonino",middleName:null,surname:"Spinelli",fullName:"Antonino Spinelli",slug:"antonino-spinelli"},{id:"79904",title:"Dr.",name:"Piero",middleName:null,surname:"Bazzi",fullName:"Piero Bazzi",slug:"piero-bazzi"},{id:"79905",title:"Dr.",name:"Matteo",middleName:null,surname:"Sacchi",fullName:"Matteo Sacchi",slug:"matteo-sacchi"},{id:"79906",title:"Prof.",name:"Marco",middleName:null,surname:"Montorsi",fullName:"Marco Montorsi",slug:"marco-montorsi"}]},{id:"26013",title:"Advances in Management of Crohn’s Disease",slug:"advances-in-management-of-crohn-s-disease",signatures:"Talha A. Malik",authors:[{id:"69268",title:"Dr.",name:"Talha",middleName:"A",surname:"Malik",fullName:"Talha Malik",slug:"talha-malik"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"63873",title:"The Role of Tropomyosin in Cardiac Function and Disease",doi:"10.5772/intechopen.81420",slug:"the-role-of-tropomyosin-in-cardiac-function-and-disease",body:'\nThe cardiovascular system plays an essential role in the viability of all vertebrate organisms by supplying oxygen and nutrients to the cells and tissues of the body and removing carbon dioxide. Because the demands of the body change rapidly, the heart must be able to respond and adapt to ever-changing environments that it confronts on a daily basis, such as developmental changes, physiological pressures, and chemical stimuli. One mechanism that is utilized by the heart is employing multiple contractile protein isoforms that can alter cardiac function under different conditions. Myosin heavy and light chains, skeletal and cardiac actin, the troponin complex, and α- and β-tropomyosin are contractile proteins that have multiple isoforms that are normally differentially expressed in the developing or adult heart. However, these changes in isoform expression during development usually occur over a time period of days to weeks. To respond to more rapidly changing conditions, such as acute stress, a faster and reversible mechanism is warranted to alter protein function, such as protein phosphorylation. The focus of this article is to address the role tropomyosin phosphorylation plays in cardiac function and to illustrate what we have learned about sarcomeric performance from these studies.
\nTropomyosin (Tpm) is encoded by four distinct genes, with each gene generating multiple isoforms through alternative splicing [1, 2]. These isoforms exhibit developmental and tissue-/cell-specific regulation by the production of striated and smooth muscle, brain, and cytoskeletal/nonmuscle mRNAs and proteins. There are three major striated muscle Tpm isoforms, referred to here as α-Tpm, β-Tpm, and γ-Tpm. The associated striated muscle Tpm proteins exhibit an alpha-helical coiled-coil dimer structure that exists as either homo- or heterodimers. Cummins and Perry [3] and Izumo et al. [4] found that the myocardium of adult small mammals expresses striated muscle α-Tpm, while fetal heart tissue expresses both α- and β-Tpm isoforms. In a more detailed analysis, we determined that the striated muscle-specific β-Tpm isoform is constitutively expressed in murine embryoid bodies during embryogenesis in utero [5]. However, the striated muscle α-Tpm isoform is not present until the day 5 embryoid body and the day 7.5 post coitus embryo. Further analyses show that both the striated muscle α- and β-Tpm isoforms are expressed during cardiogenesis (day 11–19 embryonic hearts), with the α-Tpm transcripts becoming the predominant Tpm isoform in the adult mouse heart [5]. The ratio of striated muscle α- to β-Tpm mRNAs changes from 5:1 to 60:1 as the mouse myocardium transitions from an embryonic to an adult state. γ-Tpm is expressed in slow-twitch skeletal musculature, but is not found in the heart. In addition, a cardiac specific α-Tpm isoform, called Tpm1κ, is expressed in humans and other select organisms [6, 7].
\nTpm, an α-helical coiled-coil protein dimer, plays an essential role in the regulation of contraction and relaxation in the thin filament of the sarcomere. Tpm regulates contractile activity through its interactions with actin and the troponin complex in the sarcomere. During muscle relaxation when cytoplasmic levels of calcium are low, Tpm blocks the myosin-binding site on the filamentous striated muscle actin. Upon stimulation, cytosolic calcium concentrations increase and bind to troponin C which, through its association with troponin T and I, mediates a conformational change in the Tpm position on actin. This repositioning of Tpm on actin exposes the myosin-binding site. Myosin binds to actin and triggers muscle contractile activity until the stimulation ceases, and calcium is resequestered into the sarcoplasmic reticulum.
\nPhosphorylation is a major regulator of cardiac function by affecting numerous membrane, cytoplasmic, and sarcomeric proteins. Alterations in the phosphorylation of contractile proteins, such as troponin I, myosin-binding protein C, and the regulatory light chains can affect myofilament calcium sensitivity and to physiologically regulate cardiac function [8, 9, 10, 11, 12]. Previous investigations established that Tpm is phosphorylated at serine 283, the penultimate amino acid of the protein (Figures 1 and 2) [13, 14, 15, 16, 17].
\nDiagram of the HCM Tpm180 mutation and the Tpm phosphorylation site. Diagramed in the figure is α-Tpm and the regions where TnT binds Tpm. The number above the Tpm molecule represents the amino acid residues where the hypertrophic cardiomyopathy (HCM) mutation is found and the position of the serine amino acid that is phosphorylated in Tpm.
Model of the Ser283 residues at the C-terminus of tropomyosin. C-terminal Tpm α-1 peptides are shown in dark red and green, troponin T is purple, and the N-terminal Tpm α-1 peptide is shown in gray (adapted from PDB code 2Z5H [18]). Ser283 residues are shown as yellow sticks, highlighted by the black oval. Residues in the Tpm α-1 N-terminal peptide that are positively (blue) or negatively (red) charged are highlighted. Of the two C-terminal Tpm α-1 peptides in the 2Z5H structure, one shows electron density straight through Ser283 (green helix), while the other only shows density through Met281 (dark red helix). Thus, the six C-terminal residues from the complete helix were superimposed on the incomplete helix to illustrate the putative position of Ser283 on this chain (tan extension). Note that in this model, only 1 TnT molecule is present.
This region of Tpm, specifically the carboxyl terminus, plays a critical role in its interaction with actin and troponin T (TnT), and its ability to facilitate polymerization with other Tpm molecules in a head-to-tail fashion [19, 20, 21]. Tpm phosphorylation may play a role in increasing the actin-activated myosin S1 ATPase activity, and increase the bond duration between actin-myosin interactions [22, 23]. Thus, phosphorylated Tpm may have an allosteric effect on actin to modify the actin-myosin interaction between the blocked, closed, and open states [24, 25]. Furthermore, the Tpm carboxyl region interacts with TnT, and work by our laboratory demonstrates this region dramatically affects cardiac function by regulating rates of contraction and relaxation, in addition to influencing myofilament calcium sensitivity [26]. The specific role that Tpm phosphorylation plays in influencing the physiological role of the carboxyl terminus and its interactions with the other contractile proteins in determining cardiac function was the subject of our investigations [14, 27, 28], and is being addressed in our current work [29].
\nThe serine residue at amino acid 283 is the phosphorylation site found in the three striated muscle Tpm isoforms. With respect to Tpm phosphorylation, this posttranslational process is developmentally regulated, with 60–70% phosphorylated α-Tpm being present in the murine heart during fetal and newborn stages, and a developmental decrease to approximately 30% α-Tpm phosphorylation in the adult mouse heart [28]. Interestingly, within the heart, there is differential Tpm phosphorylation among the four cardiac chambers, with atria exhibiting the highest level of phosphorylation ([30], and Sheikh and Wieczorek unpub. result). We have also found Tpm phosphorylation in human hearts; we determined Tpm is phosphorylated in substantial amounts in both the left and right ventricles, in addition to the interventricular septum. The amount of Tpm phosphorylation that occurs in human atria is currently unknown.
\nSeveral different kinases are implicated in the phosphorylation of striated muscle Tpm at the serine 283 amino acid. Investigators have identified tropomyosin kinase, protein kinase A, and protein kinase Cζ as playing potential roles in this process [15, 17, 31, 32, 33]. Also, a kinase isolated from chicken embryos has been found to phosphorylate Tpm [32]. Recent studies by our laboratory determined that casein kinase 2 can phosphorylate the striated muscle α-Tpm isoform, and this phosphorylation is specific for the S283 amino acid residue [29]. It is possible that dependent upon conditions (i.e., fetal vs. adult stages, skeletal vs. cardiac muscle, normal physiologic conditions vs. hypertrophic stress vs. physiological stress) that different kinases are activated to phosphorylate striated muscle Tpm in a myofiber-specific manner at different developmental stages and/or physiological conditions. Determining this relationship between specific kinases and their phosphorylation activity on Tpm is an area for future exploration.
\nPrevious investigations addressed the functional effect of phosphorylated Tpm using in vitro biochemical systems. As mentioned, biochemical assays, myofiber analyses, and molecular simulations indicate Tpm phosphorylation enhances the stiffness of the head-to-tail Tpm overlap region and its binding to TnT, while decreasing myofibril relaxation without significantly affecting cooperativity or altering activation kinetics [11, 22, 34]. Recently, we embarked on studies to address the physiological importance of Tpm phosphorylation in the heart using an in vivo model system [29]. The system we employed involved generating transgenic (TG) mice that expressed a phosphorylation mimetic specifically in the heart. Using the α-myosin heavy chain promoter (α-MHC), an α-Tpm cDNA construct that incorporated an aspartic acid residue replacement of serine at amino acid 283 (S283D) was expressed specifically in murine cardiomyocytes (Figure 3). Usage of an aspartic acid residue, which is negatively charged, mimics the negative charges found with phosphorylated amino acids, thus representing a pseudophosphorylation event.
\nStructure of a DNA transgenic construct showing the positions of the amino acid changes in the generation of Tpm mouse models. The striated muscle α-Tpm cDNA was ligated to the α-MHC promoter and the human growth hormone 3’ UTR. Various changes in the Tpm amino acid sequences are indicated above the construct: the HCM mutation glutamic acid (E) is substituted for glycine (G); the phosphor-mimetic aspartic acid (D) is substituted for serine (S); the nonphosphorylatable alanine (A) is substituted for serine (S).
Dilated cardiomyopathy (DCM) is a cause of significant morbidity and mortality in human patients. DCM is characterized by chamber dilation, systolic and/or diastolic dysfunction, arrhythmias, and sudden cardiac death. Results show that Tpm S283D mice that express high levels of the transgenic protein exhibit a severe dilated cardiomyopathy within 2 weeks postpartum (Figure 4). Similar to other Tpm transgenic mice, expression of the exogenous Tpm transgene leads to a reciprocal decrease in the endogenous Tpm protein, thereby demonstrating a translational feedback mechanism that regulates the total amount of Tpm protein in the cardiomyocytes [35]. This regulatory mechanism controlling Tpm protein levels is also operative when one allele of the Tpm gene is ablated [36]. In Tpm S283D mice, there is also a significant increase in the heart:body weight ratio, and these mice usually die by 1 month of age. A morphological and histological analysis of the Tpm S283D mice that express moderate levels of the transgene shows the hearts display a mild cardiomyocyte hypertrophy with limited fibrosis [29]. This moderate phenotype does not appear to progress to a more severe condition, even after 1 year. In addition, there are no significant differences in the heart:body weight ratio at either 3 or 6 months of age. Interestingly, these hearts do display significant physiological differences that are similar to those exhibited by dilated cardiomyopathic hearts.
\nControl and Tpm S283D mouse hearts. A. Whole hearts of control (left) and TG (right). B. H & E staining of NTG (left) and TG (right) cross sections. C. Measurement of heart:body weight ratio. ***P < 0.0001 NTG vs. TG [29].
To understand the functional significance of Tpm phosphorylation, we conducted various physiological measurements of cardiac and myofilament function. The work-performing heart model was used to obtain an ex vivo assessment of cardiac performance. Measurements were obtained to assess both contractile and relaxation parameters in the few high-expression mice that survived to 6 months of age, and in moderate expression mice; the results were similar regardless of the level of expression of the transgene. The values obtained show that there are no significant differences in the rates of contraction (+dP/dt) or in the time to peak pressure (TPP); however, the rates of relaxation (−dP/dt) is significantly reduced, concomitant with an increase in the half-time to relaxation (RT ½) (Table 1). Additional studies determined that the reduced relaxation performance by Tpm S283D hearts is maintained during maximal stimulation with isoproterenol, a β-adrenergic agonist that stimulates muscle contraction and relaxation. To determine whether the relationship between Ca2+ concentration and force-tension development is altered in myofibers at the sarcomeric level in Tpm S283D hearts with the phosphomimetic residue, we analyzed skinned fiber bundles from the papillary muscle of moderate and high-expression mice. No significant changes in absolute tension or normalized tension in NTG vs. TG mice are found (Table 1). Additionally, there are no significant differences in pCa50 or the Hill coefficient, a measure of the cooperative activation of the thin filament of the sarcomere.
\nMouse model | \nMaximum rate of contraction | \nMaximum rate of relaxation | \nMyofiber Ca2+ sensitivity | \nSarcomere tension development | \n
---|---|---|---|---|
α-Tpm | \n100% | \n100% | \n100% | \n100% | \n
α-Tpm S283D | \n100% | \n↓ | \n100% | \n100% | \n
α-Tpm S283A | \n100% | \n100% | \n100% | \n100% | \n
HCM α-Tpm E180G | \n100% | \n↓ | \n↑ | \n↑ | \n
HCM α-Tpm E180G/S283A | \n↑ | \n100% | \n100% | \n100% | \n
Physiological parameters of cardiac and myofiber function in Tpm mouse models.
We investigated potential signaling molecules that may play a role in the development of the DCM phenotype. The ERK1/2 signaling pathway regulates a balance between HCM and DCM [37]. Research has determined that there is a correlation between activation of the ERK1/2 pathway and HCM, whereas inhibition of the ERK pathway results in DCM [37]. Our previous investigations found that Tpm 54 DCM hearts have alterations in the levels of various kinases, including ERK1/2 and phosphor ERK1/2 [38]. In the Tpm S283D hearts, we find decreased expression of ERK1/2, phosphorylated ERK1/2, phosphorylated RSK3, and JNK1 which are members of the ERK pathway and associated with DCM. Thus, our current work on Tpm phosphorylation demonstrates that this posttranslational process not only affects cardiac function but also activates various signaling pathways associated with physiological and cardiomyopathic processes.
\nAlthough previous in vitro investigations addressed the effect of Tpm phosphorylation on myofilament function, studies have not examined the functional importance of Tpm dephosphorylation. To investigate the in vivo effect of decreased or ablated Tpm phosphorylation, we substituted serine 283 with an alanine (S283A), removing the phosphorylation site and effectively inhibiting the ability of α-Tpm to be phosphorylated. Transgenic mice were generated using the cardiac-specific myosin heavy chain promoter coupled to the α-Tpm S283A cDNA (Figure 3) [14]. Exogenous nonphosphorylatable Tpm protein expression ranged from 86 to 94%, with a concomitant reciprocal decrease in the endogenous Tpm levels. Interestingly, morphological analyses on these transgenic mouse hearts show only a very mild increase in cardiomyocyte disarray, along with a significant increase in cardiomyocyte area. Results also show no changes in the heart-to-body weight ratio, most likely due to the moderate nature of this hypertrophy. There are also no differences in the survival of these transgenic mice.
\nTo address the functional significance of Tpm dephosphorylation, we employed myofilament calcium sensitivity assays, echocardiography, and the work-performing heart model. Skinned fiber bundles from adult papillary muscle TG mice show no significant changes in absolute tension or normalized tension from the Tpm S283A hearts (Table 1) [14]. Additionally, there are no significant differences in myofiber calcium sensitivity, pCa50 value, or the Hill coefficient. These results demonstrate that the relationship between Ca2+ concentration and force-tension development is similar in control and Tpm S283A myofilaments at the sarcomeric level. The work-performing heart model allows an ex vivo functional analysis of murine cardiac physiology. To determine the physiological effects of decreased Tpm phosphorylation in the Tpm S283A hearts, contractile and relaxation parameters were determined. Results showed that there are no changes in contractile and relaxation parameters in TG hearts, either under basal conditions or when isoproterenol is administered (Table 1) [14]. To assess whether decreased Tpm phosphorylation levels has an effect on in vivo cardiac function, we performed echocardiographic analysis. No physiological changes in heart function between control and TG mice as shown by fractional shorting, cardiac output, or ejection fraction are observed. However, there are sex-specific differences in cardiac morphology: male TG animals show significant increases in left ventricular mass and left ventricular anterior and posterior wall thickness, thus indicating a hypertrophic phenotype without associated functional defects. Female TG mice do not demonstrate any altered morphological or physiological effects in their hearts. Differences in the development of cardiac hypertrophy between sexes have been reported previously [39, 40] and demonstrate the moderate nature of this hypertrophic phenotype.
\nThe lack of changes in cardiac function, myofilament cooperativity, and Ca2+ sensitivity, coupled with the development of compensated hypertrophy, lead to an investigation of possible signaling mechanisms involved in cardiac compensated or physiological hypertrophy. The Tpm S283A hearts exhibit no changes in common cardiomyopathic markers, such as β-myosin heavy chain, brain natriuretic peptide (BNP), and atrial natriuretic peptide (ANP) [14]. We did find that Tpm S283A hearts exhibit increased levels of SERCA2a protein. Total phospholamban protein expression is unchanged; however, phosphorylated phospholamban protein is increased. These alterations in Ca2+ handling proteins may be necessary to maintain normal cardiac function as the hearts compensate for the dephosphorylated Tpm that is incorporated into their myofilaments. Physiological cardiac hypertrophy is often associated with increased levels of SERCA2a, but without alterations in total phospholamban protein levels. Animals that exhibit physiological or compensated hypertrophy associated with exercise training appear to have cardiomyopathy marker and Ca2+ handling expression profiles that are similar to the Tpm S283A hearts, although the molecular expression profile during exercise training is not well elucidated. Collectively, our results demonstrate that Tpm dephosphorylation plays a role in the maintenance of a physiological or compensated hypertrophic phenotype. An area of future investigation would be to determine the level of Tpm phosphorylation in mouse hearts undergoing exercise training and exhibiting compensated cardiac hypertrophy.
\nMutations in cardiac contractile proteins are associated with the development of hypertrophic cardiomyopathy (HCM), also referred to familial hypertrophic cardiomyopathy (FHC). This disease is characterized by left and/or right ventricular hypertrophy, myocyte disarray, fibrosis, and cardiac arrhythmias that may lead to premature sudden death. At least 11 point mutations have been defined in Tpm that lead to HCM [41]. Work in our lab shows that the HCM Tpm mutation E180G in transgenic mice leads to a severe hypertrophic cardiomyopathy, similar to the phenotype exhibited by human patients [42, 43]. These TG mice exhibit significantly enlarged left ventricles, left and right atria, with disorganized myocytes and increased fibrosis. The hearts of these mice also exhibit physiological dysfunction, including decreased rates of relaxation, increased myofiber Ca2+ sensitivity, and increased maximum tension (Table 1) [43, 44]. Previous work in our laboratory found that mating these Tpm E180G mice with α-/β-Tpm chimeric mice could “rescue” double-transgenic progeny from the HCM phenotype [45]. This rescue from the severe physiological and pathological consequences of the HCM mutation was mediated by the attenuation of myofilament Ca2+ sensitivity by exchanging amino acids at the carboxy terminus from the α-Tpm to β-Tpm isoform, a region of Tpm that interacts with troponin T. This work demonstrated that alterations in the calcium response mediated through contractile proteins can prevent the pathological and physiological effects of HCM.
\nOur aforementioned investigations show that decreasing Tpm phosphorylation can lead to a compensated hypertrophic phenotype with significant increases in SERCA2a expression and phosphorylation of phospholamban. Since we determined that cardiac hypertrophy could be phenotypically rescued through modification of the response of the myocyte to Ca2+, we decided to further test this hypothesis. We generated TG mice that coexpressed the HCM α-Tpm E180G mutation with the α-Tpm S283A mutation in the same expression construct [27]. These double mutant transgenic (DMTG) mouse hearts express 50–64% exogenous Tpm protein, coupled with a concomitant decrease in endogenous Tpm protein; the amount of Tpm phosphorylation in these double TG mice was minimal, similar to the levels found in the Tpm S283A mouse hearts. A detailed histological and morphological analysis show that the DMTG hearts exhibit a phenotype that is very similar to age-matched control mice with no cardiomyocyte disarray, atrial or ventricular enlargement, or excessive fibrosis, changes which are characteristic of the Tpm E180G hearts (Figure 5) [27]. Also, there were no differences in heart weight:body weight ratios between control and DMTG animals. The addition of the S283A amino acid substitution into the HCM α-Tpm E180G mice considerably extended the life expectancy of these DMTG mice to that of wild-type control mice.
\nA. Histological studies of NTG, Tm180, and DMTG hearts at 3 months of age stained with H&E, Masson’s trichrome, and wheat germ agglutinin (WGA). Images were taken at 40×, and scale bars indicate 50 μm. B. Cardiomyocyte cross-sectional area measurements (n = 6). C. Heart weight-to-body weight (HW:BW) ratios at 3 months of age (n = 6). Error bars represent S.E. [27].
To determine whether decreased Tpm phosphorylation could improve cardiac function in a model of hypertrophic cardiomyopathy, we performed echocardiography on the DMTG mouse hearts and force-Ca2+ measurements on skinned papillary muscle fiber bundles. Results show improved systolic function with increases in ejection fraction and fractional shortening when compared with α-Tpm E180G and control littermates (Table 1) [27]. In addition, diastolic function is significantly improved in the DMTG animals, which demonstrates the rescue from the extreme diastolic dysfunction seen in the HCM α-Tpm E180G mice. We measured myofilament Ca2+ sensitivity in the DMTG mice to determine whether this parameter could also contribute to the improved cardiac function. Myofilaments from the DMTG mice show a significant decrease in Ca2+ sensitivity when compared with the HCM α-Tpm E180G measurements as indicated by a lower pCa50 value; the maximum tension and Hill coefficient are not significantly different among control, HCM α-Tpm E180G, and DMTG myofilaments. The conclusion of these results demonstrates that decreased phosphorylation of Tpm can morphologically and physiologically rescue the pathological phenotype associated with HCM.
\nTo examine potential signaling mechanisms that may be operative in DMTG animals that might play a role in the rescue of the HCM phenotype, we assayed gene expression of cardiomyopathy markers and Ca2+-handling proteins. Results show that β-myosin heavy chain (β-MHC), BNP, and ANP exhibit significantly lower levels than those found in the HCM α-Tpm E180G hearts; the levels in the DMTG animals are similar to control mice [27]. Results show there are no differences in SERCA2a levels among control, α-Tpm E180G, and DMTG animals, but there is an increase in total PLN phosphorylation in the DMTG mice. It is possible that this increase in PLN phosphorylation releases the inhibition on SERCA2a, thus stimulating Ca2+ resequestration into the sarcoplasmic reticulum to help rescue the HCM phenotype in the DMTG hearts. Other studies show that modification in contractile protein phosphorylation can improve sarcomeric and cardiac function. Deletion of the amino-terminal cardiac troponin I (TnI) domain improves cardiac contractility in aged mice, and cardiac function can be improved in restrictive cardiomyopathy mice when crossed with a TG mouse expressing a truncated amino-terminal TnI molecule [46, 47]. Also, phosphorylation of myosin light chain kinase can normalize increased Ca2+ sensitivity in an HCM model of regulatory light chain [48]. The molecular mechanism(s) that is activated by decreasing Tpm phosphorylation to improve cardiac function is unknown; however, studies suggest that the MEK1-ERK1/2 pathway may be involved in reversing the α-Tpm E180G hypertrophy [49, 50]. Another signaling pathway that might be involved in preventing the disease phenotype in the DMTG mice involves protein phosphatase 2a and casein-kinse-2-interacting protein (CKIP-1). The HCM Tpm E180G mice have increased levels of PP2a and casein kinase-2 [51, 52]. CKIP-1 and PP2a directly interact [53], which facilitates the binding of PP2a to HDAC4 to promote HDAC’s dephosphorylation. Dephosphorylation of HDAC suppresses cardiac hypertrophy and the fetal cardiac gene program [53]. If decreased Tpm phosphorylation leads to increased levels of CKIP-1 expression, then this signaling pathway may be activated in the rescue DMTG mice.
\nAs cited above, these studies collectively demonstrate a significant biological and physiological role for Tpm phosphorylation under both normal and cardiomyopathic conditions. The penultimate Tpm amino acid, serine residue 283, is located in a carboxyl region that is associated with multiple protein interactions: dimers between C-terminal Tpm molecules, C-terminal Tpm overlapping with N-terminal Tpm, and C-terminal Tpm binding with N-terminal troponin T. These multiple protein-protein interacting regions regulate myofilament function and cardiac performance, and are dramatically altered with changes in Tpm phosphorylation. Understanding the significance of developmental and disease associated changes that occur in Tpm phosphorylation is an area for future exploration. In addition, determining whether changes in Tpm phosphorylation are causative or a consequence of HCM is vital to developing therapeutic strategies for cardiovascular disease. An area of future investigation is to identify drug targets for the various kinases that phosphorylate Tpm and their downstream signaling factors so as to potentially treat various cardiomyopathic conditions.
\nThe author wishes to acknowledge the invaluable contributions of the many investigators and collaborators of the work presented in this article, especially Drs. E. Schulz, S. Rajan, and G. Jagatheesan.
\nThere are no conflicts of interest to report.
Our business values are based on those any scientist applies to their research. The values of our business are based on the same ones that all good scientists apply to their research. We have created a culture of respect and collaboration within a relaxed, friendly, and progressive atmosphere, while maintaining academic rigour.
",metaTitle:"Careers at IntechOpen",metaDescription:"Employee quote to be added",metaKeywords:null,canonicalURL:"/page/careers-at-intechopen",contentRaw:'[{"type":"htmlEditorComponent","content":"Integrity - We are consistent and dependable, always striving for precision and accuracy in the true spirit of science.
\\n\\nOpenness - We communicate honestly and transparently. We are open to constructive criticism and committed to learning from it.
\\n\\nDisruptiveness - We are eager for discovery, for new ideas and for progression. We approach our work with creativity and determination, with a clear vision that drives us forward. We look beyond today and strive for a better tomorrow.
\\n\\nIntechOpen is a dynamic, vibrant company, where exceptional people are achieving great things. We offer a creative, dedicated, committed, and passionate environment but never lose sight of the fact that science and discovery is exciting and rewarding. We constantly strive to ensure that members of our community can work, travel, meet world-renowned researchers and grow their own career and develop their own experiences.
\\n\\nIf this sounds like a place that you would like to work, whether you are at the beginning of your career or are an experienced professional, we invite you to drop us a line and tell us why you could be the right person for IntechOpen.
\\n\\nPlease send your CV and a cover letter to jobs@intechopen.com.
\\n\\nIntegrity - We are consistent and dependable, always striving for precision and accuracy in the true spirit of science.
\n\nOpenness - We communicate honestly and transparently. We are open to constructive criticism and committed to learning from it.
\n\nDisruptiveness - We are eager for discovery, for new ideas and for progression. We approach our work with creativity and determination, with a clear vision that drives us forward. We look beyond today and strive for a better tomorrow.
\n\nIntechOpen is a dynamic, vibrant company, where exceptional people are achieving great things. We offer a creative, dedicated, committed, and passionate environment but never lose sight of the fact that science and discovery is exciting and rewarding. We constantly strive to ensure that members of our community can work, travel, meet world-renowned researchers and grow their own career and develop their own experiences.
\n\nIf this sounds like a place that you would like to work, whether you are at the beginning of your career or are an experienced professional, we invite you to drop us a line and tell us why you could be the right person for IntechOpen.
\n\nPlease send your CV and a cover letter to jobs@intechopen.com.
\n\n