Cardiac myocytes

  • Armin Haunstetter
  • Markus Haass
  • Seigo Izumo
Part of the Basic Science for the Cardiologist book series (BASC, volume 5)


In recent years myocyte loss due to apoptosis has gained increasing attention in the field of cardiovascular research, as myocyte apoptosis was observed in several disease states suggesting a potential pathophysiological role. Whereas initial studies were mostly observational verifying the occurrence of apoptotic myocytes in the heart, increasingly efforts are being made to disentagle the intracellular mechanisms that induce or inhibit myocyte apoptosis. As other chapters of this book deal with the more general aspects of apoptosis, the scope of this article will be limited to summarize current knowledge of the role of apoptosis in myocardial disease and the regulatory mechanisms known to be involved in myocyte apoptosis.


Cardiac Myocytes Atrial Natriuretic Peptide Ventricular Myocytes Myocyte Apoptosis Cardiac Myocyte Apoptosis 
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  1. 1.
    Olivetti G, Quaini F, Sala R, Lagrasta C, Corradi D, Bonacina E, Gambert SR, Cigola E Anversa P. Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol 1996;28:2005–16.PubMedCrossRefGoogle Scholar
  2. 2.
    Itoh G, Tamura J, Suzuki M, Suzuki Y, Ikeda H, Koike M, Nomura M, Jie T, Ito K. DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gel electrophoresis. Am J Pathol 1995; 146:1325–31.PubMedGoogle Scholar
  3. 3.
    Bardales RH, Hailey LS, Xie SS, Schaefer RF, Hsu SM In situ apoptosis assay for the detection of early acute myocardial infarction. Am J Pathol 1996;149:821–9.PubMedGoogle Scholar
  4. 4.
    Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki LM. Apoptosis in human acute myocardial infarction. Circulation 1997;95:320–3.PubMedGoogle Scholar
  5. 5.
    Veinot JP, Gattinger DA, and Fliss H. Early apoptosis in human myocardial infarcts. Hum Pathol 1997;28:485–92.PubMedCrossRefGoogle Scholar
  6. 6.
    Kajstura J, Cheng W, Reiss K, Clark WA, Sonnenblick EH, Krajewski S, Reed JC, Olivetti G, Anversa P. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest 1996;74:86–107.PubMedGoogle Scholar
  7. 7.
    Bialik S, Geenen DL, Sasson IE, Cheng R, Homer JW, Evans SM, Lord EM, Koch CJ, Kitsis RN. Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53. J Clin Invest 1997;100:1363–72.PubMedGoogle Scholar
  8. 8.
    Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X. Cytochrome c and ATP-dependent formation of Apaf-l/Caspase-9 complex initiates an apoptotic protease cascade. Cell 1997;91:479–89.PubMedCrossRefGoogle Scholar
  9. 9.
    Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 1997; 185:1481–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 1994;94:1621–8.PubMedGoogle Scholar
  11. 11.
    Fliss H, Gattinger D. Apoptosis in ischemic and reperfused rat myocardium. Circ Res 1996;79:949–56.PubMedGoogle Scholar
  12. 12.
    Black SC, Huang JQ, Rezaiefar P, Radinovic S, Eberhart A, Nicholson DW, Rodger IW. Co-localization of the cysteine protease caspase-3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in the rat. J Mol Cell Cardiol 1998;30:733–42.PubMedCrossRefGoogle Scholar
  13. 13.
    Maulik N, Yoshida T, Engelman RM, Deaton D, Flack III JE, Rousou JA, Das DK. Ischemic preconditioning attenuates apoptotic cell death associated with ischemia/reperfusion. Mol Cell Biochem 1998; 186:139–45.PubMedCrossRefGoogle Scholar
  14. 14.
    Elsasser A, Schlepper M, Klovekorn WP, Cai WJ, Zimmermann R, Muller KD, Strasser R, Kostin S, Gagel C, Munkei B, Schaper W, Schaper J. Hibernating myocardium: an incomplete adaptation to. ischemia. Circulation 1997;96:2920–31.PubMedGoogle Scholar
  15. 15.
    Yaoita H, Ogawa K, Maehara K, Maruyama Y. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation 1998;97:276–81.PubMedGoogle Scholar
  16. 16.
    Olivetti G, Kajstura J, Cheng W, Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewski S, Reed JC, Anversa P. Apoptosis in the failing human heart. N Engl J Med 1997;336:1131–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996;335:1182–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Mallat Z, Tedgui A, Fontaliran F, Frank R, Durigon M, Fontaine G. Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med 1996;335:1190–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P. Stretch-induced programmed myocyte cell death. J Clin Invest 1995;96:2247–59.PubMedGoogle Scholar
  20. 20.
    Teiger E, Than VD, Richard L, Wisnewsky C, Tea BS, Gaboury L, Tremblay J. Schwartz K, Hamet P. Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest 1996;97:2891–7.PubMedGoogle Scholar
  21. 21.
    Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the b-adrenergic pathway. Circulation 1998;98:1329–1334.PubMedGoogle Scholar
  22. 22.
    Wu CF, Bishopric NH, and Pratt RE. Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem 1997;272:14860–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Kajstura J, Cigola E, Malhotra A, Li P, Cheng W, Meggs LG, Anversa P. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Mol Cell Cardiol 1997;29:859–70.PubMedCrossRefGoogle Scholar
  24. 24.
    Majno G, Joris L. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 1995;146:3–15.PubMedGoogle Scholar
  25. 25.
    Yue TL, Wang C, Romanic AM, Kikly K, Keller P, De Wolf WE, Hart TK, Thomas HC, Storer B, Gu JL, Wang X, Feuerstein GZ. Staurosporine-induced apoptosis in cardiomyocytes: A potential role of caspase-3. J Mol Cell Cardiol 1998;30:495–507.PubMedCrossRefGoogle Scholar
  26. 26.
    Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, Glembotski CC, Quintana PJ, Sabbadini RA. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 1996;98:2854–65.PubMedGoogle Scholar
  27. 27.
    Ohno M, Takemura G, Ohno A, Misao J, Hayakawa Y, Minatoguchi S, Fujiwara T, Fujiwara H. “Apoptotic” myocytes in infarct area in rabbit hearts may be oncotic myocytes with DNA fragmentation. Circulation 1998;98:1422–30.PubMedGoogle Scholar
  28. 28.
    Li Q, Li B, Wang X, Leri A, Jana KP, Liu Y, Kajstura J, Baserga R, Anversa P. Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J Clin Invest 1997; 100:1991–9.PubMedGoogle Scholar
  29. 29.
    Buerke M, Murohara T, Skurk C, Nuss C, Tomaselli K, Lefer AM. Cardioprotective effect of insulin-like growth factor 1 in myocardial ischemia followed by reperfusion, Proc Natl Acad Sci U SA 1995;92:8031–5.CrossRefGoogle Scholar
  30. 30.
    Tanaka M, Ito H, Adachi S, Akimoto H, Nishikawa T, Kasajima T, Marumo F, Hiroe M. Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ Res 1994;75:426–33.PubMedGoogle Scholar
  31. 31.
    Long X, Boluyt MO, Hipolito ML, Lundberg MS, Zheng JS, O’Neill L, Cirielli C, Lakatta EG, Crow MT. p53 and the hypoxia-induced apoptosis of cultured neonatal rat cardiac myocytes. J Clin Invest 1997;99:2635–43.PubMedGoogle Scholar
  32. 32.
    Sharov VG, Sabbah HN, Shimoyama H, Goussev AV, Lesch M, Goldstein S. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. Am J Pathol 1996;148:141–9.PubMedGoogle Scholar
  33. 33.
    Szabolcs M, Michler RE, Yang X, Aji W, Roy D, Athan E, Sciacca RR, Minanov OP, Cannon PJ. Apoptosis of cardiac myocytes during cardiac allograft rejection. Relation to induction of nitric oxide synthase. Circulation 1996;94:1665–73.PubMedGoogle Scholar
  34. 34.
    Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Tanaka M, Shiojima 1, Hiroi Y, Yazaki Y. Oxidative stress activates extracellular signal-regulated kinases through src and ras in cultured cardiac myocytes of neonatal rats [In Process Citation]. J Clin Invest 1997;100:1813–21.PubMedGoogle Scholar
  35. 35.
    Sawyer DB, Fukazawa R, Arstall MA, Keliy RA. Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane. Circ Res 1999;84:257–65.PubMedGoogle Scholar
  36. 36.
    Ing DJ, Zang J, Dzau VJ, Webster KA, Bishopric NH. Modulation of cytokine-induced cardiac myocyte apoptosis by nitric oxide, Bak, Bcl-x. Circ Res 1998;84:21–33.Google Scholar
  37. 37.
    Comstock KL, Krown KA, Page MT, Martin D, Ho P, Pedraza M, Castro EN, Nakajima N, Glembotski CC, Quintana PJE, Sabbadini RA. LPS-induced TNF-a release from and apoptosis in rat cardiomyocytes: Obligatory role of CD14 in mediating the LPS response. J Mol Cell Cardiol 1998;30:2761–75.PubMedCrossRefGoogle Scholar
  38. 38.
    Sheng Z, Knowlton K, Chen J, Hoshijima M, Brown JH, Chien KR. Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J Biol Chem 1997;272:5783–91.PubMedCrossRefGoogle Scholar
  39. 39.
    Geng Y, Ishikawa Y, Vatner DE., Wagner TE, Bishop SP, Vatner SF, Homcy CJ. Apoptosis of cardiac myocytes in Gsa transgenic mice. Circ Res 1998;84;34–42.Google Scholar
  40. 40.
    Zechner D, Craig R, Hanford DS, McDonough PM, Sabbadini RA, Glembotski CC. MKK6 activates myocardial cell NF-kB and inhibits apoptosis in a p38 mitogen-activated protein kinase-dependent manner. J Biol Chem 1998;273:8232–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Wang Y, Huang S, Sah VP, Ross J, Brown JH, Han J, Chien KR. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. J Biol Chem 1998;273:2161–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Kirshenbaum LA, de Moissac D. The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation 1997;96:1580–5.PubMedGoogle Scholar
  43. 43.
    Kirshenbaum LA, Schneider MD. Adenovirus EIA represses cardiac gene transcription and reactivates DNA synthesis in ventricular myocytes, via alternative pocket protein-and p300-binding domains. J Biol Chem 1995;270:7791–4.PubMedCrossRefGoogle Scholar
  44. 44.
    Kirshenbaum LA, Abdellatif M, Chakraborty S, Schneider MD. Human E2F-1 reactivates cell cycle progression in ventricular myocytes and represses cardiac gene transcription. Dev Biol 1996;179:402–11.PubMedCrossRefGoogle Scholar
  45. 45.
    Agah R, Kirshenbaum LA, Abdellatif M, Truong LD, Chakraborty S, Michael LH, Schneider MD. Adenoviral delivery of E2F-1 directs cell cycle reentry and p53-independent apoptosis in postmitotic adult myocardium in vivo. J Clin Invest 1997;100:2722–8.PubMedGoogle Scholar
  46. 46.
    Mackay K, Mochly-Rosen D. An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia. J Biol Chem 1999;274:6272–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Yue TL, Ma XL, Wang X, Romanic AM, Liu GL, Louden C, Gu JL, Kumar S, Poste G, Ruffolo RR, Feuerstein GZ. Possible involvement of stress-activated protein kinase signaling pathway and Fas receptor expression in prevention of ischemia/reperfusion-induced cardiomyocyte apoptosis by carvediioi. Circ Res 1998;82:166–74.PubMedGoogle Scholar
  48. 48.
    Fairbairn LJ, Cowling GJ, Reipert BM Dexter TM. Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors. Cell 1993;74:823–32.PubMedCrossRefGoogle Scholar
  49. 49.
    Wang L, Ma W, Markovich R, Chen J, Wang PH. Regulation of cardiomyocyte apoptotic signaling by insulin-like growth factor I. Circ Res 1998;83:516–22.PubMedGoogle Scholar
  50. 50.
    Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 1993;362:847–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B. A model for p53-induced apoptosis. Nature 1997;389:300–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Jost CA, Marin MC, Kaelin WG. p73 is a human p53-related protein that can induce apoptosis. Nature 1997;389:191–4.PubMedCrossRefGoogle Scholar
  53. 53.
    Michel T, Feron O. Nitric oxide synthases: Which, where, how, and why? J Clin Invest 1997;100:2146–52.PubMedGoogle Scholar
  54. 54.
    Pinsky DJ, Cai B, Yang X, Rodriguez C, Sciacca RR, Cannon PJ. The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synathase antagonism or transforming growth factor b. J Clin Invest 1995;95:677–85.PubMedGoogle Scholar
  55. 55.
    Kawaguchi H, Shin WS, Wang Y, Inukai M, Kato M, Matsuo-Okai Y, Sakamoto A, Uehara Y, Kaneda Y, Toyo-oka T. In vivo gene transfection of human endothelial cell nitic oxide synthase in cardiomyocytes causes apoptosis-like cell death. Circulation 1997;95:2441–7.PubMedGoogle Scholar
  56. 56.
    Koglin J, Granville DJ, Glysing-Jensen T, Mudgett JS, Carthy CM, McManus BM, Russell ME. Attenuated acute cardiac rejection in NOS2-/-recipients correlates with reduced apoptosis. Circulation 1999;99:836–42.PubMedGoogle Scholar
  57. 57.
    Torre-Amione G, Kapadia S, Lee J, Bies RD, Lebovitz R, Mann DL. Expression and functional significance of tumor necrosis factor receptors in human myocardium. Circulation 1995;92:1487–93.PubMedGoogle Scholar
  58. 58.
    Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM. The receptor for the cytotoxic ligand TRAIL. Science 1997;276:111–3.PubMedCrossRefGoogle Scholar
  59. 59.
    Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997;277:818–21.PubMedCrossRefGoogle Scholar
  60. 60.
    Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, Mann DL. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation 1996;93:704–11.PubMedGoogle Scholar
  61. 61.
    Battling B, Hoffmann J, Holtz J, Schulz R, Heusch G, Darmer D. Quantification of cardioprotective gene expression in porcine short-term hibernating myocardium. J Mol Cell Cardiol 1999;31:147–58.CrossRefGoogle Scholar
  62. 62.
    Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman AM. Dilated cardiotnyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 1997;81:627–35.PubMedGoogle Scholar
  63. 63.
    Felzen B, Shilkrut M, Less H, Sarapov 1, Maor G, Coleman R, Robinson RB, Berke G, Binah O. Fas (CD95/Apo-l)-mediated damage to ventricular myocytes induced by cytotoxic T lymphocytes from perforin-deficient mice. Circ Res 1998;82:438–50.PubMedGoogle Scholar
  64. 64.
    Srinivasula SM, Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y, Fernandes-Alnemri T, Croce CM, Litwack G, Tomaselli KJ, Armstrong RC, Alnemri ES. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFRl-induced apoptosis. J Biol Chem 1997, 272:18542–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Koseki T, Inohara N, Chen S, Nunez G. ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases. Proc Natl Acad Sci USA 1998;95:5156–60.PubMedCrossRefGoogle Scholar
  66. 66.
    Yeh WC, Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, Ng M, Wakeham A, Khoo W, Mitchell K, El-Deiry WS, Lowe SW, Goeddel DV, Mak TW. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 1998;279:1954–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P, Wallach D. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apol, and DR3 and is lethal prenatally. Immunity 1998;9:267–76.PubMedCrossRefGoogle Scholar
  68. 68.
    Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281:1309–12.PubMedCrossRefGoogle Scholar
  69. 69.
    Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X. Cytochrome c and ATP-dependent formation of apaf-l/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997;91:479–89.PubMedCrossRefGoogle Scholar
  70. 70.
    Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett R, Aebersold R, Siderovski DP, Penninger JM, Kroemer G. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999:397:441–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Schmiedl A, Schnabel PA, Mall G, Gebhard MM, Hunnemann DH, Richter J, Bretschneider HJ. The surface to volume ratio of mitochondria, a suitable parameter for evaluating mitochondrial swelling. Correlations during the course of myocardial global ischemia. Virchows Arch A Pathol Anat Histopathol 1990;4I6:305–15.CrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Armin Haunstetter
    • 1
    • 2
  • Markus Haass
    • 1
    • 2
  • Seigo Izumo
    • 1
    • 2
  1. 1.Universität HeidelbergHeidelbergGermany
  2. 2.Harvard Medical SchoolBostonUSA

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