Skip to main content

Advertisement

SpringerLink
Log in

Role of apoptosis in cardiovascular disease

  • Cell Death and Disease
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Apoptosis plays a key role in the pathogenesis in a variety of cardiovascular diseases due to loss of terminally differentiated cardiac myocytes. Cardiac myocytes undergoing apoptosis have been identified in tissue samples from patients suffering from myocardial infarction, diabetic cardiomyopathy, and end-stage congestive heart failure. Apoptosis is a highly regulated program of cell death and can be mediated by death receptors in the plasma membrane, as well as the mitochondria and the endoplasmic reticulum. The cell death program is activated in cardiac myocytes by various stressors including cytokines, increased oxidative stress and DNA damage. Many studies have demonstrated that inhibition of apoptosis is cardioprotective and can prevent the development of heart failure. This review provides a current overview of the evidence of apoptosis in cardiovascular diseases and discusses the molecular pathways involved in cardiac myocyte apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Reggiori F, Klionsky DJ (2005) Autophagosomes: biogenesis from scratch? Curr Opin Cell Biol 17:415–422. doi:10.1016/j.ceb.2005.06.007

    Article  PubMed  CAS  Google Scholar 

  2. Kitsis RN, Peng CF, Cuervo AM (2007) Eat your heart out. Nat Med 13:539–541. doi:10.1038/nm0507-539

    Article  PubMed  CAS  Google Scholar 

  3. Schweichel JU, Merker HJ (1973) The morphology of various types of cell death in prenatal tissues. Teratology 7:253–266. doi:10.1002/tera.1420070306

    Article  Google Scholar 

  4. Searle J, Kerr JF, Bishop CJ (1982) Necrosis and apoptosis: distinct modes of cell death with fundamentally different significance. Pathol Annu 17(Pt 2):229–259

    PubMed  Google Scholar 

  5. Kerr JF (1971) Shrinkage necrosis: a distinct mode of cellular death. J Pathol 105:13–20. doi:10.1002/path.1711050103

    Article  PubMed  CAS  Google Scholar 

  6. Majno G, Joris I (1995) Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 146:3–15

    PubMed  CAS  Google Scholar 

  7. Rich T, Watson CJ, Wyllie A (1999) Apoptosis: the germs of death. Nat Cell Biol 1:E69–E71. doi:10.1038/11038

    Article  PubMed  CAS  Google Scholar 

  8. Savill J, Fadok V (2000) Corpse clearance defines the meaning of cell death. Nature 407:784–788. doi:10.1038/35037722

    Article  PubMed  CAS  Google Scholar 

  9. Olivetti G, Quaini F, Sala R et al (1996) 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 28:2005–2016. doi:10.1006/jmcc.1996.0193

    Article  PubMed  CAS  Google Scholar 

  10. Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki LM (1997) Apoptosis in human acute myocardial infarction. Circulation 95:320–323

    PubMed  CAS  Google Scholar 

  11. Narula J, Haider N, Virmani R et al (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335:1182–1189. doi:10.1056/NEJM199610173351603

    Article  PubMed  CAS  Google Scholar 

  12. Aharinejad S, Andrukhova O, Lucas T et al (2008) Programmed cell death in idiopathic dilated cardiomyopathy is mediated by suppression of the apoptosis inhibitor Apollon. Ann Thorac Surg 86:109–114. doi:10.1016/j.athoracsur.2008.03.057 discussion 114

    Article  PubMed  Google Scholar 

  13. Cheng W, Kajstura J, Nitahara JA et al (1996) Programmed myocyte cell death affects the viable myocardium after infarction in rats. Exp Cell Res 226:316–327. doi:10.1006/excr.1996.0232

    Article  PubMed  CAS  Google Scholar 

  14. Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL (1994) Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 94:1621–1628. doi:10.1172/JCI117504

    Article  PubMed  CAS  Google Scholar 

  15. Gao HK, Yin Z, Zhou N, Feng XY, Gao F, Wang HC (2008) Glycogen synthase kinase 3 inhibition protects the heart from acute ischemia–reperfusion injury via inhibition of inflammation and apoptosis. J Cardiovasc Pharmacol 52:286–292. doi:10.1097/FJC.0b013e318186a84d

    Article  PubMed  CAS  Google Scholar 

  16. Kubota T, McTiernan CF, Frye CS et al (1997) Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 81:627–635

    PubMed  CAS  Google Scholar 

  17. Bryant D, Becker L, Richardson J et al (1998) Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 97:1375–1381

    PubMed  CAS  Google Scholar 

  18. Sayen MR, Gustafsson AB, Sussman MA, Molkentin JD, Gottlieb RA (2003) Calcineurin transgenic mice have mitochondrial dysfunction and elevated superoxide production. Am J Physiol Cell Physiol 284:C562–C570

    PubMed  CAS  Google Scholar 

  19. Wang J, Silva JP, Gustafsson CM, Rustin P, Larsson NG (2001) Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression. Proc Natl Acad Sci USA 98:4038–4043. doi:10.1073/pnas.061038798

    Article  PubMed  CAS  Google Scholar 

  20. Kockx MM, De Meyer GR, Muhring J, Jacob W, Bult H, Herman AG (1998) Apoptosis and related proteins in different stages of human atherosclerotic plaques. Circulation 97:2307–2315

    PubMed  CAS  Google Scholar 

  21. Clarke MC, Littlewood TD, Figg N et al (2008) Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration. Circ Res 102:1529–1538. doi:10.1161/CIRCRESAHA.108.175976

    Article  PubMed  CAS  Google Scholar 

  22. Matsumura K, Jeremy RW, Schaper J, Becker LC (1998) Progression of myocardial necrosis during reperfusion of ischemic myocardium. Circulation 97:795–804

    PubMed  CAS  Google Scholar 

  23. Takemura G, Ohno M, Hayakawa Y et al (1998) Role of apoptosis in the disappearance of infiltrated and proliferated interstitial cells after myocardial infarction. Circ Res 82:1130–1138

    PubMed  CAS  Google Scholar 

  24. Kannel WB, Hjortland M, Castelli WP (1974) Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 34:29–34. doi:10.1016/0002-9149(74)90089-7

    Article  PubMed  CAS  Google Scholar 

  25. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ (2002) Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes 51:1938–1948. doi:10.2337/diabetes.51.6.1938

    Article  PubMed  CAS  Google Scholar 

  26. Li Z, Zhang T, Dai H et al (2007) Involvement of endoplasmic reticulum stress in myocardial apoptosis of streptozocin-induced diabetic rats. J Clin Biochem Nutr 41:58–67. doi:10.3164/jcbn.2007008

    Article  PubMed  CAS  Google Scholar 

  27. Mukamal KJ, Nesto RW, Cohen MC et al (2001) Impact of diabetes on long-term survival after acute myocardial infarction: comparability of risk with prior myocardial infarction. Diabetes Care 24:1422–1427. doi:10.2337/diacare.24.8.1422

    Article  PubMed  CAS  Google Scholar 

  28. Backlund T, Palojoki E, Saraste A et al (2004) Sustained cardiomyocyte apoptosis and left ventricular remodelling after myocardial infarction in experimental diabetes. Diabetologia 47:325–330. doi:10.1007/s00125-003-1311-5

    Article  PubMed  CAS  Google Scholar 

  29. Kuethe F, Sigusch HH, Bornstein SR, Hilbig K, Kamvissi V, Figulla HR (2007) Apoptosis in patients with dilated cardiomyopathy and diabetes: a feature of diabetic cardiomyopathy? Horm Metab Res 39:672–676. doi:10.1055/s-2007-985823

    Article  PubMed  CAS  Google Scholar 

  30. Cai L, Kang YJ (2001) Oxidative stress and diabetic cardiomyopathy: a brief review. Cardiovasc Toxicol 1:181–193. doi:10.1385/CT:1:3:181

    Article  PubMed  CAS  Google Scholar 

  31. Song Y, Wang J, Li Y et al (2005) Cardiac metallothionein synthesis in streptozotocin-induced diabetic mice, and its protection against diabetes-induced cardiac injury. Am J Pathol 167:17–26

    PubMed  CAS  Google Scholar 

  32. Ye G, Metreveli NS, Ren J, Epstein PN (2003) Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. Diabetes 52:777–783. doi:10.2337/diabetes.52.3.777

    Article  PubMed  CAS  Google Scholar 

  33. Guerra S, Leri A, Wang X et al (1999) Myocyte death in the failing human heart is gender dependent. Circ Res 85:856–866

    PubMed  CAS  Google Scholar 

  34. Wencker D, Chandra M, Nguyen K et al (2003) A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 111:1497–1504

    PubMed  CAS  Google Scholar 

  35. Thorburn A (2004) Death receptor-induced cell killing. Cell Signal 16:139–144. doi:10.1016/j.cellsig.2003.08.007

    Article  PubMed  CAS  Google Scholar 

  36. Liao X, Wang X, Gu Y, Chen Q, Chen LY (2005) Involvement of death receptor signaling in mechanical stretch-induced cardiomyocyte apoptosis. Life Sci 77:160–174. doi:10.1016/j.lfs.2004.11.029

    Article  PubMed  CAS  Google Scholar 

  37. Levine B, Kalman J, Mayer L, Fillit HM, Packer M (1990) Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323:236–241

    PubMed  CAS  Google Scholar 

  38. Dutka DP, Elborn JS, Delamere F, Shale DJ, Morris GK (1993) Tumour necrosis factor alpha in severe congestive cardiac failure. Br Heart J 70:141–143. doi:10.1136/hrt.70.2.141

    Article  PubMed  CAS  Google Scholar 

  39. Ferrari R, Bachetti T, Confortini R et al (1995) Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation 92:1479–1486

    PubMed  CAS  Google Scholar 

  40. Testa M, Yeh M, Lee P et al (1996) Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J Am Coll Cardiol 28:964–971. doi:10.1016/S0735-1097(96)00268-9

    Article  PubMed  CAS  Google Scholar 

  41. Giroir BP, Johnson JH, Brown T, Allen GL, Beutler B (1992) The tissue distribution of tumor necrosis factor biosynthesis during endotoxemia. J Clin Invest 90:693–698. doi:10.1172/JCI115939

    Article  PubMed  CAS  Google Scholar 

  42. Kapadia S, Lee J, Torre-Amione G, Birdsall HH, Ma TS, Mann DL (1995) Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration. J Clin Invest 96:1042–1052. doi:10.1172/JCI118090

    Article  PubMed  CAS  Google Scholar 

  43. Jeremias I, Kupatt C, Martin-Villalba A et al (2000) Involvement of CD95/Apo1/Fas in cell death after myocardial ischemia. Circulation 102:915–920

    PubMed  CAS  Google Scholar 

  44. Torre-Amione G, Kapadia S, Lee J et al (1996) Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation 93:704–711

    PubMed  CAS  Google Scholar 

  45. Doyama K, Fujiwara H, Fukumoto M et al (1996) Tumour necrosis factor is expressed in cardiac tissues of patients with heart failure. Int J Cardiol 54:217–225. doi:10.1016/0167-5273(96)02607-1

    Article  PubMed  CAS  Google Scholar 

  46. Gilles S, Zahler S, Welsch U, Sommerhoff CP, Becker BF (2003) Release of TNF-alpha during myocardial reperfusion depends on oxidative stress and is prevented by mast cell stabilizers. Cardiovasc Res 60:608–616. doi:10.1016/j.cardiores.2003.08.016

    Article  PubMed  CAS  Google Scholar 

  47. Tanaka M, Ito H, Adachi S et al (1994) Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ Res 75:426–433

    PubMed  CAS  Google Scholar 

  48. Meldrum DR (1998) Tumor necrosis factor in the heart. Am J Physiol 274:R577–R595

    PubMed  CAS  Google Scholar 

  49. Seko Y, Kayagaki N, Seino K, Yagita H, Okumura K, Nagai R (2002) Role of Fas/FasL pathway in the activation of infiltrating cells in murine acute myocarditis caused by Coxsackievirus B3. J Am Coll Cardiol 39:1399–1403. doi:10.1016/S0735-1097(02)01776-X

    Article  PubMed  CAS  Google Scholar 

  50. Lee P, Sata M, Lefer DJ, Factor SM, Walsh K, Kitsis RN (2003) Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia–reperfusion in vivo. Am J Physiol Heart Circ Physiol 284:H456–H463

    PubMed  CAS  Google Scholar 

  51. Li Y, Takemura G, Kosai K et al (2004) Critical roles for the Fas/Fas ligand system in postinfarction ventricular remodeling and heart failure. Circ Res 95:627–636. doi:10.1161/01.RES.0000141528.54850.bd

    Article  PubMed  CAS  Google Scholar 

  52. Gomez L, Chavanis N, Argaud L et al (2005) Fas-independent mitochondrial damage triggers cardiomyocyte death after ischemia–reperfusion. Am J Physiol Heart Circ Physiol 289:H2153–H2158. doi:10.1152/ajpheart.00165.2005

    Article  PubMed  CAS  Google Scholar 

  53. Bhuiyan MS, Takada Y, Shioda N, Moriguchi S, Kasahara J, Fukunaga K (2008) Cardioprotective effect of vanadyl sulfate on ischemia/reperfusion-induced injury in rat heart in vivo is mediated by activation of protein kinase B and induction of FLICE-inhibitory protein. Cardiovasc Ther 26:10–23

    PubMed  CAS  Google Scholar 

  54. Niu J, Azfer A, Deucher MF, Goldschmidt-Clermont PJ, Kolattukudy PE (2006) Targeted cardiac expression of soluble FAS prevents the development of heart failure in mice with cardiac-specific expression of MCP-1. J Mol Cell Cardiol 40:810–820. doi:10.1016/j.yjmcc.2006.03.010

    Article  PubMed  CAS  Google Scholar 

  55. Scarabelli TM, Stephanou A, Pasini E et al (2002) Different signaling pathways induce apoptosis in endothelial cells and cardiac myocytes during ischemia/reperfusion injury. Circ Res 90:745–748. doi:10.1161/01.RES.0000015224.07870.9A

    Article  PubMed  CAS  Google Scholar 

  56. Gustafsson AB, Tsai JG, Logue SE, Crow MT, Gottlieb RA (2004) Apoptosis repressor with caspase recruitment domain protects against cell death by interfering with Bax activation. J Biol Chem 279:21233–21238. doi:10.1074/jbc.M400695200

    Article  PubMed  CAS  Google Scholar 

  57. Chen M, Won DJ, Krajewski S, Gottlieb RA (2002) Calpain and mitochondria in ischemia/reperfusion injury. J Biol Chem 277:29181–29186. doi:10.1074/jbc.M204951200

    Article  PubMed  CAS  Google Scholar 

  58. Hamacher-Brady A, Brady NR, Logue SE et al (2007) Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 14:146–157. doi:10.1038/sj.cdd.4401936

    Article  PubMed  CAS  Google Scholar 

  59. Iliodromitis EK, Lazou A, Kremastinos DT (2007) Ischemic preconditioning: protection against myocardial necrosis and apoptosis. Vasc Health Risk Manag 3:629–637

    PubMed  CAS  Google Scholar 

  60. Imahashi K, Schneider MD, Steenbergen C, Murphy E (2004) Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. Circ Res 95:734–741. doi:10.1161/01.RES.0000143898.67182.4c

    Article  PubMed  CAS  Google Scholar 

  61. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219. doi:10.1016/S0092-8674(04)00046-7

    Article  PubMed  CAS  Google Scholar 

  62. Huang DC, Strasser A (2000) BH3-Only proteins-essential initiators of apoptotic cell death. Cell 103:839–842. doi:10.1016/S0092-8674(00)00187-2

    Article  PubMed  CAS  Google Scholar 

  63. Reeve JL, Szegezdi E, Logue SE et al (2007) Distinct mechanisms of cardiomyocyte apoptosis induced by doxorubicin and hypoxia converge on mitochondria and are inhibited by Bcl-xL. J Cell Mol Med 11:509–520. doi:10.1111/j.1582-4934.2007.00042.x

    Article  PubMed  CAS  Google Scholar 

  64. Kirshenbaum LA, de Moissac D (1997) The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation 96:1580–1585

    PubMed  CAS  Google Scholar 

  65. Zhang D, Mott JL, Chang SW, Stevens M, Mikolajczak P, Zassenhaus HP (2005) Mitochondrial DNA mutations activate programmed cell survival in the mouse heart. Am J Physiol Heart Circ Physiol 288:H2476–H2483. doi:10.1152/ajpheart.00670.2004

    Article  PubMed  CAS  Google Scholar 

  66. Brocheriou V, Hagege AA, Oubenaissa A et al (2000) Cardiac functional improvement by a human Bcl-2 transgene in a mouse model of ischemia/reperfusion injury. J Gene Med 2:326–333. doi:10.1002/1521-2254(200009/10)2:5<326::AID-JGM133>3.0.CO;2-1

    Article  PubMed  CAS  Google Scholar 

  67. Chen Z, Chua CC, Ho YS, Hamdy RC, Chua BH (2001) Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am J Physiol Heart Circ Physiol 280:H2313–H2320

    PubMed  CAS  Google Scholar 

  68. Gustafsson AB, Gottlieb RA (2007) Bcl-2 family members and apoptosis, taken to heart. Am J Physiol Cell Physiol 292:C45–C51

    Article  PubMed  CAS  Google Scholar 

  69. Milner DJ, Taffet GE, Wang X et al (1999) The absence of desmin leads to cardiomyocyte hypertrophy and cardiac dilation with compromised systolic function. J Mol Cell Cardiol 31:2063–2076. doi:10.1006/jmcc.1999.1037

    Article  PubMed  CAS  Google Scholar 

  70. Weisleder N, Taffet GE, Capetanaki Y (2004) Bcl-2 overexpression corrects mitochondrial defects and ameliorates inherited desmin null cardiomyopathy. Proc Natl Acad Sci USA 101:769–774. doi:10.1073/pnas.0303202101

    Article  PubMed  CAS  Google Scholar 

  71. Karmazyn M, Moffat MP (1993) Role of Na+/H+ exchange in cardiac physiology and pathophysiology: mediation of myocardial reperfusion injury by the pH paradox. Cardiovasc Res 27:915–924. doi:10.1093/cvr/27.6.915

    Article  PubMed  CAS  Google Scholar 

  72. Zhu L, Yu Y, Chua BH, Ho YS, Kuo TH (2001) Regulation of sodium–calcium exchange and mitochondrial energetics by Bcl-2 in the heart of transgenic mice. J Mol Cell Cardiol 33:2135–2144. doi:10.1006/jmcc.2001.1476

    Article  PubMed  CAS  Google Scholar 

  73. Rouslin W, Erickson JL, Solaro RJ (1986) Effects of oligomycin and acidosis on rates of ATP depletion in ischemic heart muscle. Am J Physiol 250:H503–H508

    PubMed  CAS  Google Scholar 

  74. Imahashi K, Schneider M, Steenbergen C, Murphy E (2004) BCL-2 reduces acidification and the fall in ATP during Ischaemia. Cardiovasc J S Afr 15:S3

    Google Scholar 

  75. Kubli DA, Quinsay MN, Huang C, Lee Y, Gustafsson AB (2008) Bnip3 functions as a mitochondrial sensor of oxidative stress during myocardial ischemia and reperfusion. Am J Physiol Heart Circ Physiol 295(5):H2025–H2031

    Article  PubMed  CAS  Google Scholar 

  76. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14–3-3 not BCL-X(L). Cell 87:619–628. doi:10.1016/S0092-8674(00)81382-3

    Article  PubMed  CAS  Google Scholar 

  77. Wei MC, Zong WX, Cheng EH et al (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730. doi:10.1126/science.1059108

    Article  PubMed  CAS  Google Scholar 

  78. Kubli DA, Ycaza JE, Gustafsson AB (2007) Bnip3 mediates mitochondrial dysfunction and cell death through Bax and Bak. Biochem J 405:407–415. doi:10.1042/BJ20070319

    Article  PubMed  CAS  Google Scholar 

  79. Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB (2001) BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 15:1481–1486. doi:10.1101/gad.897601

    Article  PubMed  CAS  Google Scholar 

  80. Capano M, Crompton M (2006) Bax translocates to mitochondria of heart cells during simulated ischaemia: involvement of AMP-activated and p38 mitogen-activated protein kinases. Biochem J 395:57–64. doi:10.1042/BJ20051654

    Article  PubMed  CAS  Google Scholar 

  81. Hamacher-Brady A, Brady NR, Gottlieb RA (2006) Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem 281:29776–29787. doi:10.1074/jbc.M603783200

    Article  PubMed  CAS  Google Scholar 

  82. Hochhauser E, Kivity S, Offen D et al (2003) Bax ablation protects against myocardial ischemia–reperfusion injury in transgenic mice. Am J Physiol Heart Circ Physiol 284:H2351–H2359

    PubMed  CAS  Google Scholar 

  83. Diwan A, Krenz M, Syed FM et al (2007) Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. J Clin Invest 117:2825–2833. doi:10.1172/JCI32490

    Article  PubMed  CAS  Google Scholar 

  84. Bruick RK (2000) Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci USA 97:9082–9087. doi:10.1073/pnas.97.16.9082

    Article  PubMed  CAS  Google Scholar 

  85. Yurkova N, Shaw J, Blackie K et al (2008) The cell cycle factor E2F-1 activates Bnip3 and the intrinsic death pathway in ventricular myocytes. Circ Res 102:472–479. doi:10.1161/CIRCRESAHA.107.164731

    Article  PubMed  CAS  Google Scholar 

  86. Frazier DP, Wilson A, Graham RM, Thompson JW, Bishopric NH, Webster KA (2006) Acidosis regulates the stability, hydrophobicity, and activity of the BH3-only protein Bnip3. Antioxid Redox Signal 8:1625–1634. doi:10.1089/ars.2006.8.1625

    Article  PubMed  CAS  Google Scholar 

  87. Regula KM, Ens K, Kirshenbaum LA (2002) Inducible expression of BNIP3 provokes mitochondrial defects and hypoxia-mediated cell death of ventricular myocytes. Circ Res 91:226–231. doi:10.1161/01.RES.0000029232.42227.16

    Article  PubMed  CAS  Google Scholar 

  88. Vande VC, Cizeau J, Dubik D et al (2000) BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol 20:5454–5468. doi:10.1128/MCB.20.15.5454-5468.2000

    Article  Google Scholar 

  89. Diwan A, Wansapura J, Syed FM, Matkovich SJ, Lorenz JN, Dorn GW II (2008) Nix-mediated apoptosis links myocardial fibrosis, cardiac remodeling, and hypertrophy decompensation. Circulation 117:396–404. doi:10.1161/CIRCULATIONAHA.107.727073

    Article  PubMed  CAS  Google Scholar 

  90. Chen M, He H, Zhan S, Krajewski S, Reed JC, Gottlieb RA (2001) Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion. J Biol Chem 276:30724–30728. doi:10.1074/jbc.M103701200

    Article  PubMed  CAS  Google Scholar 

  91. Murriel CL, Churchill E, Inagaki K, Szweda LI, Mochly-Rosen D (2004) Protein kinase Cdelta activation induces apoptosis in response to cardiac ischemia and reperfusion damage: a mechanism involving BAD and the mitochondria. J Biol Chem 279:47985–47991. doi:10.1074/jbc.M405071200

    Article  PubMed  CAS  Google Scholar 

  92. Latif N, Khan MA, Birks E et al (2000) Upregulation of the Bcl-2 family of proteins in end stage heart failure. J Am Coll Cardiol 35:1769–1777. doi:10.1016/S0735-1097(00)00647-1

    Article  PubMed  CAS  Google Scholar 

  93. Di Napoli P, Taccardi AA, Grilli A et al (2003) Left ventricular wall stress as a direct correlate of cardiomyocyte apoptosis in patients with severe dilated cardiomyopathy. Am Heart J 146:1105–1111. doi:10.1016/S0002-8703(03)00445-9

    Article  PubMed  Google Scholar 

  94. Baldi A, Abbate A, Bussani R et al (2002) Apoptosis and post-infarction left ventricular remodeling. J Mol Cell Cardiol 34:165–174. doi:10.1006/jmcc.2001.1498

    Article  PubMed  CAS  Google Scholar 

  95. Sharma AK, Dhingra S, Khaper N, Singal PK (2007) Activation of apoptotic processes during transition from hypertrophy to heart failure in guinea pigs. Am J Physiol Heart Circ Physiol 293:H1384–H1390. doi:10.1152/ajpheart.00553.2007

    Article  PubMed  CAS  Google Scholar 

  96. Li P, Nijhawan D, Budihardjo I et al (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489. doi:10.1016/S0092-8674(00)80434-1

    Article  PubMed  CAS  Google Scholar 

  97. Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW (2002) Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell 9:423–432. doi:10.1016/S1097-2765(02)00442-2

    Article  PubMed  CAS  Google Scholar 

  98. Jiang X, Wang X (2000) Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem 275:31199–31203. doi:10.1074/jbc.C000405200

    Article  PubMed  CAS  Google Scholar 

  99. Pacher P, Szabo C (2007) Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovasc Drug Rev 25:235–260. doi:10.1111/j.1527-3466.2007.00018.x

    Article  PubMed  CAS  Google Scholar 

  100. de Boer RA, van Veldhuisen DJ, van der Wijk J et al (2000) Additional use of immunostaining for active caspase 3 and cleaved actin and PARP fragments to detect apoptosis in patients with chronic heart failure. J Card Fail 6:330–337. doi:10.1054/jcaf.2000.20457

    Article  PubMed  Google Scholar 

  101. Vahsen N, Cande C, Briere JJ et al (2004) AIF deficiency compromises oxidative phosphorylation. EMBO J 23:4679–4689. doi:10.1038/sj.emboj.7600461

    Article  PubMed  CAS  Google Scholar 

  102. Joza N, Oudit GY, Brown D et al (2005) Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy. Mol Cell Biol 25:10261–10272. doi:10.1128/MCB.25.23.10261-10272.2005

    Article  PubMed  CAS  Google Scholar 

  103. van Empel VP, Bertrand AT, van der Nagel R et al (2005) Downregulation of apoptosis-inducing factor in harlequin mutant mice sensitizes the myocardium to oxidative stress-related cell death and pressure overload-induced decompensation. Circ Res 96:e92–e101. doi:10.1161/01.RES.0000172081.30327.28

    Article  PubMed  CAS  Google Scholar 

  104. Norberg E, Gogvadze V, Ott M et al (2008) An increase in intracellular Ca(2+) is required for the activation of mitochondrial calpain to release AIF during cell death. Cell Death Differ 15(12):1857–1864

    Article  PubMed  CAS  Google Scholar 

  105. Daugas E, Susin SA, Zamzami N et al (2000) Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J 14:729–739

    PubMed  CAS  Google Scholar 

  106. Halestrap AP (2006) Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans 34:232–237. doi:10.1042/BST20060232

    Article  PubMed  CAS  Google Scholar 

  107. Garcia-Rivas Gde J, Carvajal K, Correa F, Zazueta C (2006) Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br J Pharmacol 149:829–837. doi:10.1038/sj.bjp.0706932

    Article  PubMed  CAS  Google Scholar 

  108. Wang J, Zhang Z, Hu Y et al (2007) SEA0400, a novel Na(+)/Ca(2 +) exchanger inhibitor, reduces calcium overload induced by ischemia and reperfusion in mouse ventricular myocytes. Physiol Res 56:17–23

    PubMed  CAS  Google Scholar 

  109. Kim GT, Chun YS, Park JW, Kim MS (2003) Role of apoptosis-inducing factor in myocardial cell death by ischemia–reperfusion. Biochem Biophys Res Commun 309:619–624. doi:10.1016/j.bbrc.2003.08.045

    Article  PubMed  CAS  Google Scholar 

  110. Song ZF, Ji XP, Li XX, Wang SJ, Wang SH, Zhang Y (2008) Inhibition of the activity of poly (ADP-ribose) polymerase reduces heart ischaemia/reperfusion injury via suppressing JNK-mediated AIF translocation. J Cell Mol Med 12:1220–1228. doi:10.1111/j.1582-4934.2008.00183.x

    Article  PubMed  CAS  Google Scholar 

  111. Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J 16:6914–6925. doi:10.1093/emboj/16.23.6914

    Article  PubMed  CAS  Google Scholar 

  112. Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388:300–304. doi:10.1038/40901

    Article  PubMed  CAS  Google Scholar 

  113. Liu HR, Gao E, Hu A et al (2005) Role of Omi/HtrA2 in apoptotic cell death after myocardial ischemia and reperfusion. Circulation 111:90–96. doi:10.1161/01.CIR.0000151613.90994.17

    Article  PubMed  CAS  Google Scholar 

  114. Bhuiyan MS, Fukunaga K (2007) Inhibition of HtrA2/Omi ameliorates heart dysfunction following ischemia/reperfusion injury in rat heart in vivo. Eur J Pharmacol 557:168–177. doi:10.1016/j.ejphar.2006.10.067

    Article  PubMed  CAS  Google Scholar 

  115. Chua CC, Gao J, Ho YS et al (2007) Overexpression of IAP-2 attenuates apoptosis and protects against myocardial ischemia/reperfusion injury in transgenic mice. Biochim Biophys Acta 1773:577–583

    Article  PubMed  CAS  Google Scholar 

  116. Ikeda S, Ozaki K (1997) Action of mitochondrial endonuclease G on DNA damaged by L-ascorbic acid, peplomycin, and cis-diamminedichloroplatinum (II). Biochem Biophys Res Commun 235:291–294. doi:10.1006/bbrc.1997.6786

    Article  PubMed  CAS  Google Scholar 

  117. Javadov S, Choi A, Rajapurohitam V, Zeidan A, Basnakian AG, Karmazyn M (2008) NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition. Cardiovasc Res 77:416–424. doi:10.1093/cvr/cvm039

    Article  PubMed  CAS  Google Scholar 

  118. Bahi N, Zhang J, Llovera M, Ballester M, Comella JX, Sanchis D (2006) Switch from caspase-dependent to caspase-independent death during heart development: essential role of endonuclease G in ischemia-induced DNA processing of differentiated cardiomyocytes. J Biol Chem 281:22943–22952. doi:10.1074/jbc.M601025200

    Article  PubMed  CAS  Google Scholar 

  119. Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7:880–885. doi:10.1038/sj.embor.7400779

    Article  PubMed  CAS  Google Scholar 

  120. Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115:2656–2664. doi:10.1172/JCI26373

    Article  PubMed  CAS  Google Scholar 

  121. Okada K, Minamino T, Tsukamoto Y et al (2004) Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110:705–712. doi:10.1161/01.CIR.0000137836.95625.D4

    Article  PubMed  Google Scholar 

  122. Szegezdi E, Duffy A, O’Mahoney ME et al (2006) ER stress contributes to ischemia-induced cardiomyocyte apoptosis. Biochem Biophys Res Commun 349:1406–1411. doi:10.1016/j.bbrc.2006.09.009

    Article  PubMed  CAS  Google Scholar 

  123. Thuerauf DJ, Marcinko M, Gude N, Rubio M, Sussman MA, Glembotski CC (2006) Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes. Circ Res 99:275–282. doi:10.1161/01.RES.0000233317.70421.03

    Article  PubMed  CAS  Google Scholar 

  124. Azfer A, Niu J, Rogers LM, Adamski FM, Kolattukudy PE (2006) Activation of endoplasmic reticulum stress response during the development of ischemic heart disease. Am J Physiol Heart Circ Physiol 291:H1411–H1420. doi:10.1152/ajpheart.01378.2005

    Article  PubMed  CAS  Google Scholar 

  125. Jackson CV, McGrath GM, Tahiliani AG, Vadlamudi RV, McNeill JH (1985) A functional and ultrastructural analysis of experimental diabetic rat myocardium.Manifestation of a cardiomyopathy. Diabetes 34:876–883. doi:10.2337/diabetes.34.9.876

    Article  PubMed  CAS  Google Scholar 

  126. Hamada H, Suzuki M, Yuasa S et al (2004) Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice. Mol Cell Biol 24:8007–8017. doi:10.1128/MCB.24.18.8007-8017.2004

    Article  PubMed  CAS  Google Scholar 

  127. Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC (2003) Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 22:8608–8618. doi:10.1038/sj.onc.1207108

    Article  PubMed  CAS  Google Scholar 

  128. Qi X, Vallentin A, Churchill E, Mochly-Rosen D (2007) deltaPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart. J Mol Cell Cardiol 43:420–428. doi:10.1016/j.yjmcc.2007.07.061

    Article  PubMed  CAS  Google Scholar 

  129. Toth A, Jeffers JR, Nickson P et al (2006) Targeted deletion of puma attenuates cardiomyocyte death and improves cardiac function during ischemia-reperfusion. Am J Physiol Heart Circ Physiol 291(1):H52–H60

    Article  PubMed  CAS  Google Scholar 

  130. Nickson P, Toth A, Erhardt P (2007) PUMA is critical for neonatal cardiomyocyte apoptosis induced by endoplasmic reticulum stress. Cardiovasc Res 73:48–56. doi:10.1016/j.cardiores.2006.10.001

    Article  PubMed  CAS  Google Scholar 

  131. Scorrano L, Oakes SA, Opferman JT et al (2003) BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300:135–139. doi:10.1126/science.1081208

    Article  PubMed  CAS  Google Scholar 

  132. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490. doi:10.1016/S0092-8674(00)81589-5

    Article  PubMed  CAS  Google Scholar 

  133. Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501. doi:10.1016/S0092-8674(00)81590-1

    Article  PubMed  CAS  Google Scholar 

  134. Date T, Mochizuki S, Belanger AJ et al (2003) Differential effects of membrane and soluble Fas ligand on cardiomyocytes: role in ischemia/reperfusion injury. J Mol Cell Cardiol 35:811–821. doi:10.1016/S0022-2828(03)00139-1

    Article  PubMed  CAS  Google Scholar 

  135. Haudek SB, Taffet GE, Schneider MD, Mann DL (2007) TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways. J Clin Invest 117:2692–2701. doi:10.1172/JCI29134

    Article  PubMed  CAS  Google Scholar 

  136. Kalai M, Lamkanfi M, Denecker G et al (2003) Regulation of the expression and processing of caspase-12. J Cell Biol 162:457–467. doi:10.1083/jcb.200303157

    Article  PubMed  CAS  Google Scholar 

  137. Bajaj G, Sharma RK (2006) TNF-alpha-mediated cardiomyocyte apoptosis involves caspase-12 and calpain. Biochem Biophys Res Commun 345:1558–1564. doi:10.1016/j.bbrc.2006.05.059

    Article  PubMed  CAS  Google Scholar 

  138. Gyan E, Frisan E, Beyne-Rauzy O et al (2008) Spontaneous and Fas-induced apoptosis of low-grade MDS erythroid precursors involves the endoplasmic reticulum. Leukemia 22:1864–1873. doi:10.1038/leu.2008.172

    Article  PubMed  CAS  Google Scholar 

  139. Breckenridge DG, Stojanovic M, Marcellus RC, Shore GC (2003) Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J Cell Biol 160:1115–1127. doi:10.1083/jcb.200212059

    Article  PubMed  CAS  Google Scholar 

  140. Mathai JP, Germain M, Shore GC (2005) BH3-only BIK regulates BAX, BAK-dependent release of Ca2+ from endoplasmic reticulum stores and mitochondrial apoptosis during stress-induced cell death. J Biol Chem 280:23829–23836. doi:10.1074/jbc.M500800200

    Article  PubMed  CAS  Google Scholar 

  141. Nakai A, Yamaguchi O, Takeda T et al (2007) The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13:619–624. doi:10.1038/nm1574

    Article  PubMed  CAS  Google Scholar 

  142. Matsui Y, Takagi H, Qu X et al (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 100:914–922. doi:10.1161/01.RES.0000261924.76669.36

    Article  PubMed  CAS  Google Scholar 

  143. Zhu H, Tannous P, Johnstone JL et al (2007) Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 117:1782–1793. doi:10.1172/JCI27523

    Article  PubMed  CAS  Google Scholar 

  144. Yan L, Vatner DE, Kim SJ et al (2005) Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci USA 102:13807–13812. doi:10.1073/pnas.0506843102

    Article  PubMed  CAS  Google Scholar 

  145. Yousefi S, Perozzo R, Schmid I et al (2006) Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 8:1124–1132. doi:10.1038/ncb1482

    Article  PubMed  CAS  Google Scholar 

  146. Pyo JO, Jang MH, Kwon YK et al (2005) Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem 280:20722–20729. doi:10.1074/jbc.M413934200

    Article  PubMed  CAS  Google Scholar 

  147. Pattingre S, Tassa A, Qu X et al (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939. doi:10.1016/j.cell.2005.07.002

    Article  PubMed  CAS  Google Scholar 

  148. Maiuri MC, Criollo A, Tasdemir E et al (2007) BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy 3:374–376

    PubMed  CAS  Google Scholar 

  149. Rashmi R, Pillai SG, Vijayalingam S, Ryerse J, Chinnadurai G (2008) BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 27:1366–1375. doi:10.1038/sj.onc.1210783

    Article  PubMed  CAS  Google Scholar 

  150. Akar U, Chaves-Reyez A, Barria M et al (2008) Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy 4:669–679

    PubMed  CAS  Google Scholar 

  151. Ray R, Chen G, Vande VC et al (2000) BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3 (BH3) domain at both mitochondrial and nonmitochondrial sites. J Biol Chem 275:1439–1448. doi:10.1074/jbc.275.2.1439

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This manuscript was supported by a Scientist Development Award from AHA, and NIH grant HL087023 to Å. B. G.

Author information

Authors and Affiliations

  1. BioScience Center, San Diego State University, 5500 Campanile Drive, San Diego, CA, 92182-4650, USA

    Youngil Lee & Åsa B. Gustafsson

Authors
  1. Youngil Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Åsa B. Gustafsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Åsa B. Gustafsson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, Y., Gustafsson, Å.B. Role of apoptosis in cardiovascular disease. Apoptosis 14, 536–548 (2009). https://doi.org/10.1007/s10495-008-0302-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-008-0302-x

Keywords

Search

Navigation