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Review

Decoding telomere protein Rap1: Its telomeric and nontelomeric functions and potential implications in diabetic cardiomyopathy

, , , , &
Pages 1765-1773 | Received 02 Jun 2017, Accepted 19 Aug 2017, Published online: 14 Sep 2017

References

  • de Lange T. Protection of mammalian telomeres. Oncogene. 2002;21:532-40. doi:10.1038/sj.onc.1205080. PMID:11850778
  • de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19:2100-10. doi:10.1101/gad.1346005. PMID:16166375
  • Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet. 2008;42:301-34. doi:10.1146/annurev.genet.41.110306.130350. PMID:18680434
  • Shore D, Nasmyth K. Purification and cloning of a DNA binding protein from yeast that binds to both silencer and activator elements. Cell. 1987;51:721-32. doi:10.1016/0092-8674(87)90095-X. PMID:3315231
  • Konig P, Giraldo R, Chapman L, Rhodes D. The crystal structure of the DNA-binding domain of yeast RAP1 in complex with telomeric DNA. Cell. 1996;85:125-36. doi:10.1016/S0092-8674(00)81088-0. PMID:8620531
  • Li B, Oestreich S, de Lange T. Identification of human Rap1: implications for telomere evolution. Cell. 2000;101:471-83. doi:10.1016/S0092-8674(00)80858-2. PMID:10850490
  • Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. Telomere end-replication problem and cell aging. J Mol Biol. 1992;225:951-60. doi:10.1016/0022-2836(92)90096-3. PMID:1613801
  • Brouilette S, Singh RK, Thompson JR, Goodall AH, Samani NJ. White cell telomere length and risk of premature myocardial infarction. Arterioscler Thromb Vasc Biol. 2003;23:842-6. doi:10.1161/01.ATV.0000067426.96344.32. PMID:12649083
  • Benetos A, Gardner JP, Zureik M, Labat C, Xiaobin L, Adamopoulos C, Temmar M, Bean KE, Thomas F, Aviv A. Short telomeres are associated with increased carotid atherosclerosis in hypertensive subjects. Hypertension. 2004;43:182-5. doi:10.1161/01.HYP.0000113081.42868.f4. PMID:14732735
  • Shay JW, Wright WE. Role of telomeres and telomerase in cancer. Semin Cancer Biol. 2011;21:349-53. doi:10.1016/j.semcancer.2011.10.001. PMID:22015685
  • Grunstein M. Molecular model for telomeric heterochromatin in yeast. Curr Opin Cell Biol. 1997;9:383-7. doi:10.1016/S0955-0674(97)80011-7. PMID:9159071
  • Kaizer H, Connelly CJ, Bettridge K, Viggiani C, Greider CW. Regulation of Telomere Length Requires a Conserved N-Terminal Domain of Rif2 in Saccharomyces cerevisiae. Genetics. 2015;201:573-86. doi:10.1534/genetics.115.177899. PMID:26294668
  • Moretti P, Freeman K, Coodly L, Shore D. Evidence that a complex of SIR proteins interacts with the silencer and telomere-binding protein RAP1. Genes Dev. 1994;8:2257-69. doi:10.1101/gad.8.19.2257. PMID:7958893
  • van Steensel B, de Lange T. Control of telomere length by the human telomeric protein TRF1. Nature. 1997;385:740-3. doi:10.1038/385740a0. PMID:9034193
  • O'Connor MS, Safari A, Liu D, Qin J, Songyang Z. The human Rap1 protein complex and modulation of telomere length. J Biol Chem. 2004;279:28585-91. doi:10.1074/jbc.M312913200. PMID:15100233
  • Li B, de Lange T. Rap1 affects the length and heterogeneity of human telomeres. Mol Biol Cell. 2003;14:5060-8. doi:10.1091/mbc.E03-06-0403. PMID:14565979
  • Kabir S, Hockemeyer D, de Lange T. TALEN gene knockouts reveal no requirement for the conserved human shelterin protein Rap1 in telomere protection and length regulation. Cell Reports. 2014;9:1273-80. doi:10.1016/j.celrep.2014.10.014. PMID:25453752
  • Sfeir A, Kabir S, van Overbeek M, Celli GB, de Lange T. Loss of Rap1 induces telomere recombination in the absence of NHEJ or a DNA damage signal. Science. 2010;327:1657-61. doi:10.1126/science.1185100. PMID:20339076
  • Martinez P, Gomez-Lopez G, Garcia F, Mercken E, Mitchell S, Flores JM, de Cabo R, Blasco MA. RAP1 protects from obesity through its extratelomeric role regulating gene expression. Cell Reports. 2013;3:2059-74. doi:10.1016/j.celrep.2013.05.030. PMID:23791526
  • Lu W, Zhang Y, Liu D, Songyang Z, Wan M. Telomeres-structure, function, and regulation. Exp Cell Res. 2013;319:133-41. doi:10.1016/j.yexcr.2012.09.005. PMID:23006819
  • Celli GB, de Lange T. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nat Cell Biol. 2005;7:712-8. doi:10.1038/ncb1275. PMID:15968270
  • van Steensel B, Smogorzewska A, de Lange T. TRF2 protects human telomeres from end-to-end fusions. Cell. 1998;92:401-13. doi:10.1016/S0092-8674(00)80932-0. PMID:9476899
  • Celli GB, Denchi EL, de Lange T. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination. Nat Cell Biol. 2006;8:885-90. doi:10.1038/ncb1444. PMID:16845382
  • Rai R, Chen Y, Lei M, Chang S. TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nat Commun. 2016;7:10881. doi:10.1038/ncomms10881. PMID:26941064
  • Chen Y, Rai R, Zhou ZR, Kanoh J, Ribeyre C, Yang Y, Zheng H, Damay P, Wang F, Tsujii H, et al. A conserved motif within RAP1 has diversified roles in telomere protection and regulation in different organisms. Nat Structural Mol Biol. 2011;18:213-21. doi:10.1038/nsmb.1974.
  • Hegan DC, Lu Y, Stachelek GC, Crosby ME, Bindra RS, Glazer PM. Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A. 2010;107:2201-6. doi:10.1073/pnas.0904783107. PMID:20133863
  • Azad GK, Tomar RS. The multifunctional transcription factor Rap1: a regulator of yeast physiology. Frontiers Biosci (Landmark edition). 2016;21:918-30. doi:10.2741/4429.
  • Martinez P, Thanasoula M, Carlos AR, Gomez-Lopez G, Tejera AM, Schoeftner S, Dominguez O, Pisano DG, Tarsounas M, Blasco MA. Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites. Nat Cell Biol. 2010;12:768-80. doi:10.1038/ncb2081. PMID:20622869
  • Hanaoka S, Nagadoi A, Yoshimura S, Aimoto S, Li B, de Lange T, Nishimura Y. NMR structure of the hRap1 Myb motif reveals a canonical three-helix bundle lacking the positive surface charge typical of Myb DNA-binding domains. J Mol Biol. 2001;312:167-75. doi:10.1006/jmbi.2001.4924. PMID:11545594
  • Janoušková E, Nečasová I, Pavloušková J, Zimmermann M, Hluchý M, Marini V, Nováková M, Hofr C. Human Rap1 modulates TRF2 attraction to telomeric DNA. Nucleic Acids Res. 2015;43:2691-700. doi:10.1093/nar/gkv097. PMID:25675958
  • Khan S, Chuturgoon AA, Naidoo DP. Telomeres and atherosclerosis. Cardiovascular J Africa. 2012;23:563-71. doi:10.5830/CVJA-2012-056.
  • Armanios M. Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Invest. 2013;123:996-1002. doi:10.1172/JCI66370. PMID:23454763
  • Eisele PS, Salatino S, Sobek J, Hottiger MO, Handschin C. The peroxisome proliferator-activated receptor gamma coactivator 1alpha/beta (PGC-1) coactivators repress the transcriptional activity of NF-kappaB in skeletal muscle cells. J Biol Chem. 2013;288:2246-60. doi:10.1074/jbc.M112.375253. PMID:23223635
  • Patten IS, Arany Z. PGC-1 coactivators in the cardiovascular system. Trends Endocrinol Metab TEM. 2012;23:90-7. doi:10.1016/j.tem.2011.09.007. PMID:22047951
  • Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, Cooper M, Kotton D, Fabian AJ, Walkey C, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature. 2011;470:359-65. doi:10.1038/nature09787. PMID:21307849
  • Hardy CF, Sussel L, Shore D. A RAP1-interacting protein involved in transcriptional silencing and telomere length regulation. Genes Dev. 1992;6:801-14. doi:10.1101/gad.6.5.801. PMID:1577274
  • O'Connor MS, Safari A, Liu D, Qin J, Songyang Z. The human Rap1 protein complex and modulation of telomere length. J Biol Chem. 2004;279:28585-91. doi:10.1074/jbc.M312913200. PMID:15100233
  • Shore D. RAP1: a protean regulator in yeast. Trends Genet. 1994;10:408-12. doi:10.1016/0168-9525(94)90058-2. PMID:7809947
  • Chambers A, Stanway C, Tsang JS, Henry Y, Kingsman AJ, Kingsman SM. ARS binding factor 1 binds adjacent to RAP1 at the UASs of the yeast glycolytic genes PGK and PYK1. Nucleic Acids Res. 1990;18:5393-9. doi:10.1093/nar/18.18.5393. PMID:2120676
  • Nishizawa M, Araki R, Teranishi Y. Identification of an upstream activating sequence and an upstream repressible sequence of the pyruvate kinase gene of the yeast Saccharomyces cerevisiae. Mol Cell Biol. 1989;9:442-51. doi:10.1128/MCB.9.2.442. PMID:2651900
  • Butler G, Dawes IW, McConnell DJ. TUF factor binds to the upstream region of the pyruvate decarboxylase structural gene (PDC1) of Saccharomyces cerevisiae. Mol Gen Genet. 1990;223:449-56. doi:10.1007/BF00264453. PMID:2270085
  • Bitter GA, Chang KK, Egan KM. A multi-component upstream activation sequence of the Saccharomyces cerevisiae glyceraldehyde-3-phosphate dehydrogenase gene promoter. Mol Gen Genet. 1991;231:22-32. doi:10.1007/BF00293817. PMID:1753943
  • Yeung F, Ramirez CM, Mateos-Gomez PA, Pinzaru A, Ceccarini G, Kabir S, Fernandez-Hernando C, Sfeir A. Nontelomeric role for Rap1 in regulating metabolism and protecting against obesity. Cell Reports. 2013;3:1847-56. doi:10.1016/j.celrep.2013.05.032. PMID:23791522
  • Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: The PPARα-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A. 1999;96:7473-8. doi:10.1073/pnas.96.13.7473. PMID:10377439
  • Costet P, Legendre C, Moré J, Edgar A, Galtier P, Pineau T. Peroxisome proliferator-activated receptor α-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. J Biol Chem. 1998;273:29577-85. doi:10.1074/jbc.273.45.29577. PMID:9792666
  • Qatanani M, Lazar MA. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes Dev. 2007;21:1443-55. doi:10.1101/gad.1550907. PMID:17575046
  • Lawrence T. The Nuclear Factor NF-κB pathway in inflammation. Cold Spring Harbor Perspect Biol. 2009;1:a001651. doi:10.1101/cshperspect.a001651.
  • Teo H, Ghosh S, Luesch H, Ghosh A, Wong ET, Malik N, Orth A, de Jesus P, Perry AS, Oliver JD, et al. Telomere-independent Rap1 is an IKK adaptor and regulates NF-kappaB-dependent gene expression. Nat Cell Biol. 2010;12:758-67. doi:10.1038/ncb2080. PMID:20622870
  • Ghosh AS, Tergaonkar V. Telomeres and inflammation: Rap1 joins the ends? Cell cycle (Georgetown, Tex). 2010;9:3834-5. doi:10.4161/cc.9.19.13383. PMID:20890110
  • Ghosh A, Saginc G, Leow SC, Khattar E, Shin EM, Yan TD, Wong M, Zhang Z, Li G, Sung WK, et al. Telomerase directly regulates NF-kappaB-dependent transcription. Nat Cell Biol. 2012;14:1270-81. doi:10.1038/ncb2621. PMID:23159929
  • Cai Y, Sukhova GK, Wong HK, Xu A, Tergaonkar V, Vanhoutte PM, Tang EHC. Rap1 induces cytokine production in pro-inflammatory macrophages through NFκB signaling and is highly expressed in human atherosclerotic lesions. Cell Cycle (Georgetown, Tex). 2015;14:3580-92. doi:10.1080/15384101.2015.1100771. PMID:26505215
  • Takai KK, Hooper S, Blackwood S, Gandhi R, de Lange T. In vivo stoichiometry of shelterin components. J Biol Chem. 2010;285:1457-67. doi:10.1074/jbc.M109.038026. PMID:19864690
  • Poon MW, Yan L, Jiang D, Qin P, Tse HF, Wong IY, Wong DS, Tergaonkar V, Lian Q. Inhibition of RAP1 enhances corneal recovery following alkali injury. Invest Ophthalmol Visual Sci. 2015;56:711-21. doi:10.1167/iovs.14-15268.
  • Zhang Y, Chiu S, Liang X, Gao F, Zhang Z, Liao S, Liang Y, Chai YH, Low DJH, Tse HF, et al. Rap1-mediated nuclear factor-kappaB (NF-κB) activity regulates the paracrine capacity of mesenchymal stem cells in heart repair following infarction. Cell Death Discovery. 2015;1:15007. doi:10.1038/cddiscovery.2015.7. PMID:27551443
  • Li CX, Lo CM, Lian Q, Ng KT, Liu XB, Ma YY, Qi X, Yeung OW, Tergaonkar V, Yang XX, et al. Repressor and activator protein accelerates hepatic ischemia reperfusion injury by promoting neutrophil inflammatory response. Oncotarget. 2016;7:27711-23. doi:10.18632/oncotarget.8509. PMID:27050284
  • Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225-60. doi:10.1146/annurev.immunol.16.1.225. PMID:9597130
  • Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006;86:515-81. doi:10.1152/physrev.00024.2005. PMID:16601268
  • Monaco C, Paleolog E. Nuclear factor kappaB: a potential therapeutic target in atherosclerosis and thrombosis. Cardiovasc Res. 2004;61:671-82. doi:10.1016/j.cardiores.2003.11.038. PMID:14985064
  • Mallat Z, Tedgui A. NF-κB activation in atherosclerosis: a friend or a foe? Blood. 2004;103:754-5. doi:10.1182/blood-2003-11-3818.
  • Kanters E, Pasparakis M, Gijbels MJ, Vergouwe MN, Partouns-Hendriks I, Fijneman RJ, Clausen BE, Forster I, Kockx MM, Rajewsky K, et al. Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003;112:1176-85. doi:10.1172/JCI200318580. PMID:14561702
  • Xanthoulea S, Curfs DM, Hofker MH, de Winther MP. Nuclear factor kappa B signaling in macrophage function and atherogenesis. Curr Opin Lipidol. 2005;16:536-42. doi:10.1097/01.mol.0000180167.15820.ae. PMID:16148538
  • Libby P, Ridker PM, Hansson GK. Inflammation in Atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54:2129-38. doi:10.1016/j.jacc.2009.09.009. PMID:19942084
  • Rosa CM, Xavier NP, Henrique Campos D, Fernandes AA, Cezar MD, Martinez PF, Cicogna AC, Gimenes C, Gimenes R, Okoshi MP, et al. Diabetes mellitus activates fetal gene program and intensifies cardiac remodeling and oxidative stress in aged spontaneously hypertensive rats. Cardiovascular Diabetol. 2013;12:152. doi:10.1186/1475-2840-12-152.
  • Tabak O, Gelisgen R, Erman H, Erdenen F, Muderrisoglu C, Aral H, Uzun H. Oxidative lipid, protein, and DNA damage as oxidative stress markers in vascular complications of diabetes mellitus. Clin Invest Med. 2011;34:E163-71. doi:10.25011/cim.v34i3.15189. PMID:21631993
  • Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813-20. doi:10.1038/414813a. PMID:11742414
  • Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787-90. doi:10.1038/35008121. PMID:10783895
  • Santos L, Escande C, Denicola A. Potential modulation of Sirtuins by oxidative stress. Oxidative Med Cell Longevity. 2016;2016:9831825. doi:10.1155/2016/9831825.
  • Merksamer PI, Liu Y, He W, Hirschey MD, Chen D, Verdin E. The sirtuins, oxidative stress and aging: an emerging link. Aging (Albany NY). 2013;5:144-50. doi:10.18632/aging.100544. PMID:23474711
  • Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004;303:2011-5. doi:10.1126/science.1094637. PMID:14976264
  • Lee JH, Song MY, Song EK, Kim EK, Moon WS, Han MK, Park JW, Kwon KB, Park BH. Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway. Diabetes. 2009;58:344-51. doi:10.2337/db07-1795. PMID:19008341
  • Luo K, Vega-Palas MA, Grunstein M. Rap1-Sir4 binding independent of other Sir, yKu, or histone interactions initiates the assembly of telomeric heterochromatin in yeast. Genes Dev. 2002;16:1528-39. doi:10.1101/gad.988802. PMID:12080091
  • Lieb JD, Liu X, Botstein D, Brown PO. Promoter-specific binding of Rap1 revealed by genome-wide maps of protein-DNA association. Nat Genetics. 2001;28:327-34. doi:10.1038/ng569. PMID:11455386
  • Adamczyk J, Deregowska A, Skoneczny M, Skoneczna A, Kwiatkowska A, Potocki L, Rawska E, Pabian S, Kaplan J, Lewinska A, et al. Adaptive response to chronic mild ethanol stress involves ROS, sirtuins and changes in chromosome dosage in wine yeasts. Oncotarget. 2016;7:29958-76. doi:10.18632/oncotarget.8673. PMID:27074556
  • Salpea KD, Talmud PJ, Cooper JA, Maubaret CG, Stephens JW, Abelak K, Humphries SE. Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. Atherosclerosis. 2010;209:42-50. doi:10.1016/j.atherosclerosis.2009.09.070. PMID:19889414
  • Swanson MJ, Baribault ME, Israel JN, Bae NS. Telomere protein RAP1 levels are affected by cellular aging and oxidative stress. Biomedical Reports. 2016;5:181-7. doi:10.3892/br.2016.707. PMID:27446538
  • Berglund K, Reynolds CA, Ploner A, Gerritsen L, Hovatta I, Pedersen NL, Hägg S. Longitudinal decline of leukocyte telomere length in old age and the association with sex and genetic risk. Aging (Albany NY). 2016;8:1398-407. doi:10.18632/aging.100995. PMID:27391763
  • Wulaningsih W, Watkins J, Matsuguchi T, Hardy R. Investigating the associations between adiposity, life course overweight trajectories, and telomere length. Aging (Albany NY). 2016;8:2689-701. doi:10.18632/aging.101036. PMID:27650676
  • Peng H, Zhu Y, Yeh F, Cole SA, Best LG, Lin J, Blackburn E, Devereux RB, Roman MJ, Lee ET, et al. Impact of biological aging on arterial aging in American Indians: findings from the Strong Heart Family Study. Aging (Albany NY). 2016;8:1583-92. doi:10.18632/aging.101013. PMID:27540694
  • De Vusser K, Pieters N, Janssen B, Lerut E, Kuypers D, Jochmans I, Monbaliu D, Pirenne J, Nawrot T, Naesens M. Telomere length, cardiovascular risk and arteriosclerosis in human kidneys: an observational cohort study. Aging (Albany NY). 2015;7:766-75. doi:10.18632/aging.100814. PMID:26539975
  • Zhao MX, Zhou B, Ling L, Xiong XQ, Zhang F, Chen Q, Li YH, Kang YM, Zhu GQ. Salusin-beta contributes to oxidative stress and inflammation in diabetic cardiomyopathy. Cell Death Dis. 2017;8(3), e2690 doi:10.1038/cddis.2017.106. PMID:28333148
  • Zhang B, Shen Q, Chen Y, Pan R, Kuang S, Liu G, Sun G, Sun X. Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy. Sci Rep. 2017;7, 44239 doi:10.1038/srep44239. PMID:28287141
  • Prakoso D, DeBlasio MJ, Qin C, Rosli S, Kiriazis H, Qian H, Du XJ, Weeks KL, Gregorevic P, McMullen JR, Ritchie, RH. Phosphoinositide 3-Kinase (p110alpha) gene delivery Limits Diabetes-induced Cardiac NADPH oxidase and cardiomyopathy in a mouse model with established Diastolic Dysfunction. Clin Sci (Lond). 2017;131:1345-60. doi:10.1042/CS20170063. PMID:28487469
  • Chang AC, Ong SG, LaGory EL, Kraft PE, Giaccia AJ, Wu JC, Blau HM. Telomere shortening and metabolic compromise underlie dystrophic cardiomyopathy. Proc Natl Acad Sci U S A. 2016;113:13120-25. doi:10.1073/pnas.1615340113. PMID:27799523
  • Gordon JW, Shaw JA, Kirshenbaum LA. Multiple facets of NF-kappaB in the heart: to be or not to NF-kappaB. Circulation Res. 2011;108:1122-32. doi:10.1161/CIRCRESAHA.110.226928. PMID:21527742
  • Kim JW, Jin YC, Kim YM, Rhie S, Kim HJ, Seo HG, Lee JH, Ha YL, Chang KC. Daidzein administration in vivo reduces myocardial injury in a rat ischemia/reperfusion model by inhibiting NF-kappaB activation. Life Sci. 2009;84:227-34. doi:10.1016/j.lfs.2008.12.005. PMID:19109981
  • Ravingerova T, Adameova A, Carnicka S, Nemcekova M, Kelly T, Matejikova J, Galatou E, Barlaka E, Lazou A. The role of PPAR in myocardial response to ischemia in normal and diseased heart. Gen Physiol Biophys. 2011;30:329-41. doi:10.4149/gpb_2011_04_329. PMID:22131314
  • Kolwicz SC, Purohit S, Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of the cardiomyocte. Circulation Res. 2013;113:603-16. doi:10.1161/CIRCRESAHA.113.302095. PMID:23948585