DOI QR코드

DOI QR Code

Apoptosis in Cardiovascular Diseases: Mechanism and Clinical Implications

  • Kim, Nam-Ho (Division of Cardiology, Department of Internal Medicine, Wonkwang University Medical School) ;
  • Kang, Peter M. (Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School)
  • 발행 : 2010.07.30

초록

Apoptosis is a tightly regulated, cell deletion process that plays an important role in various cardiovascular diseases, such as myocardial infarction, reperfusion injury, and heart failure. Since cardiomyocyte loss is the most important determinant of patient morbidity and mortality, fully understanding the regulatory mechanisms of apoptotic signaling is crucial. In fact, the inhibition of cardiac apoptosis holds promise as an effective therapeutic strategy for cardiovascular diseases. Caspase, a critical enzyme in the induction and execution of apoptosis, has been the main potential target for achieving anti-apoptotic therapy. Studies suggest, however, that a caspase-independent pathway may also play an important role in cardiac apoptosis, although the mechanism and potential significance of caspase-independent apoptosis in the heart remain poorly understood. Herein we discuss the role of apoptosis in various cardiovascular diseases, provide an update on current knowledge about the molecular mechanisms that govern apoptosis, and discuss the clinical implications of anti-apoptotic therapies.

키워드

참고문헌

  1. Saraste A, Voipio-Pulkki LM, Parvinen M, Pulkki K. Apoptosis in the heart. N Engl J Med 1997;336:1025-6; discussion 6. https://doi.org/10.1056/NEJM199704033361415
  2. Kang PM, Izumo S. Apoptosis in heart: basic mechanisms and implications in cardiovascular diseases. Trends Mol Med 2003;9:177-82. https://doi.org/10.1016/S1471-4914(03)00025-X
  3. Kang PM, Izumo S. Apoptosis and heart failure: a critical review of the literature. Circ Res 2000;86:1107-13. https://doi.org/10.1161/01.RES.86.11.1107
  4. Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 1994;94:1621-8. https://doi.org/10.1172/JCI117504
  5. Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart. N Engl J Med 1997;336:1131-41. https://doi.org/10.1056/NEJM199704173361603
  6. Olivetti G, Quaini F, Sala R, et al. 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. https://doi.org/10.1006/jmcc.1996.0193
  7. Takemura G, Ohno M, Hayakawa Y, et al. Role of apoptosis in the disappearance of infiltrated and proliferated interstitial cells after myocardial infarction. Circ Res 1998;82:1130-8. https://doi.org/10.1161/01.RES.82.11.1130
  8. Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci 1997;22:299-306. https://doi.org/10.1016/S0968-0004(97)01085-2
  9. Pop C, Salvesen GS. Human caspases: activation, specificity, and regulation. J Biol Chem 2009;284:21777-81. https://doi.org/10.1074/jbc.R800084200
  10. Zheng TS, Hunot S, Kuida K, Flavell RA. Caspase knockouts: matters of life and death. Cell Death Differ 1999;6:1043-53. https://doi.org/10.1038/sj.cdd.4400593
  11. Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 1996;86:147-57. https://doi.org/10.1016/S0092-8674(00)80085-9
  12. Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997;91:479-89. https://doi.org/10.1016/S0092-8674(00)80434-1
  13. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome cdependent activation of caspase-3. Cell 1997;90:405-13. https://doi.org/10.1016/S0092-8674(00)80501-2
  14. Nagata S. Apoptosis by death factor. Cell 1997;88:355-65. https://doi.org/10.1016/S0092-8674(00)81874-7
  15. Slee EA, Harte MT, Kluck RM, et al. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 1999;144: 281-92. https://doi.org/10.1083/jcb.144.2.281
  16. Kang PM, Haunstetter A, Aoki H, Usheva A, Izumo S. Morphological and molecular characterization of adult cardiomyocyte apoptosis during hypoxia and reoxygenation. Circ Res 2000;87:118-25. https://doi.org/10.1161/01.RES.87.2.118
  17. Yeh WC, Pompa JL, McCurrach ME, et al. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 1998;279:1954-8. https://doi.org/10.1126/science.279.5358.1954
  18. Ishiyama S, Hiroe M, Nishikawa T, et al. The Fas/Fas ligand system is involved in the pathogenesis of autoimmune myocarditis in rats. J Immunol 1998;161:4695-701.
  19. Twu C, Liu NQ, Popik W, et al. Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways. Proc Natl Acad Sci U S A 2002;99:14386-91. https://doi.org/10.1073/pnas.212327899
  20. Doyama K, Fujiwara H, Fukumoto M, et al. Tumour necrosis factor is expressed in cardiac tissues of patients with heart failure. Int J Cardiol 1996;54:217-25. https://doi.org/10.1016/0167-5273(96)02607-1
  21. Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation 1996;93:704-11. https://doi.org/10.1161/01.CIR.93.4.704
  22. Bryant D, Becker L, Richardson J, et al. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 1998;97:1375-81. https://doi.org/10.1161/01.CIR.97.14.1375
  23. Kubota T, McTiernan CF, Frye CS, et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 1997;81:627-35. https://doi.org/10.1161/01.RES.81.4.627
  24. Lee P, Sata M, Lefer DJ, Factor SM, Walsh K, Kitsis RN. Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia- reperfusion in vivo. Am J Physiol Heart Circ Physiol 2003;284: H456-63. https://doi.org/10.1152/ajpheart.00777.2002
  25. Nelson DP, Setser E, Hall DG, et al. Proinflammatory consequences of transgenic fas ligand expression in the heart. J Clin Invest 2000; 105:1199-208. https://doi.org/10.1172/JCI8212
  26. Kurrelmeyer KM, Michael LH, Baumgarten G, et al. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic- induced apoptosis in a murine model of acute myocardial infarction. Proc Natl Acad Sci U S A 2000;97:5456-61. https://doi.org/10.1073/pnas.070036297
  27. Bao Q, Shi Y. Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ 2007;14:56-65. https://doi.org/10.1038/sj.cdd.4402028
  28. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008;9:47-59. https://doi.org/10.1038/nrm2308
  29. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998;281:1322-6. https://doi.org/10.1126/science.281.5381.1322
  30. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94:491-501. https://doi.org/10.1016/S0092-8674(00)81590-1
  31. Brocheriou V, Hagege AA, Oubenaissa A, et al. Cardiac functional improvement by a human Bcl-2 transgene in a mouse model of ischemia/ reperfusion injury. J Gene Med 2000;2:326-33. https://doi.org/10.1002/1521-2254(200009/10)2:5<326::AID-JGM133>3.0.CO;2-1
  32. Chen Z, Chua CC, Ho YS, Hamdy RC, Chua BH. Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am J Physiol Heart Circ Physiol 2001;280:H2313- 20. https://doi.org/10.1152/ajpheart.2001.280.5.H2313
  33. Hochhauser E, Cheporko Y, Yasovich N, et al. Bax deficiency reduces infarct size and improves long-term function after myocardial infarction. Cell Biochem Biophys 2007;47:11-20. https://doi.org/10.1385/CBB:47:1:11
  34. Salvesen GS, Dixit VM. Caspase activation: the induced-proximity model. Proc Natl Acad Sci U S A 1999;96:10964-7. https://doi.org/10.1073/pnas.96.20.10964
  35. Sun CK, Chang LT, Sheu JJ, et al. Losartan preserves integrity of cardiac gap junctions and PGC-1 alpha gene expression and prevents cellular apoptosis in remote area of left ventricular myocardium following acute myocardial infarction. Int Heart J 2007;48:533-46. https://doi.org/10.1536/ihj.48.533
  36. Ekhterae D, Lin Z, Lundberg MS, Crow MT, Brosius FC 3rd, Nunez G. ARC inhibits cytochrome c release from mitochondria and protects against hypoxia-induced apoptosis in heart-derived H9c2 cells. Circ Res 1999;85:e70-7. https://doi.org/10.1161/01.RES.85.12.e70
  37. 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 U S A 1998;95:5156-60. https://doi.org/10.1073/pnas.95.9.5156
  38. Pyo JO, Nah J, Kim HJ, et al. Protection of cardiomyocytes from ischemic/ hypoxic cell death via Drbp1 and pMe2GlyDH in cardio-specific ARC transgenic mice. J Biol Chem 2008;283:30707-14. https://doi.org/10.1074/jbc.M804209200
  39. Han Y, Chen YS, Liu Z, et al. Overexpression of HAX-1 protects cardiac myocytes from apoptosis through caspase-9 inhibition. Circ Res 2006;99:415-23. https://doi.org/10.1161/01.RES.0000237387.05259.a5
  40. Bae S, Yalamarti B, Kang PM. Role of caspase-independent apoptosis in cardiovascular diseases. Front Biosci 2008;13:2495-503. https://doi.org/10.2741/2861
  41. Lorenzo HK, Susin SA, Penninger J, Kroemer G. Apoptosis inducing factor (AIF): a phylogenetically old, caspase-independent effector of cell death. Cell Death Differ 1999;6:516-24. https://doi.org/10.1038/sj.cdd.4400527
  42. Penninger JM, Kroemer G. Mitochondria, AIF and caspases: rivaling for cell death execution. Nat Cell Biol 2003;5:97-9. https://doi.org/10.1038/ncb0203-97
  43. Cande C, Cecconi F, Dessen P, Kroemer G. Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death? J Cell Sci 2002;115:4727-34. https://doi.org/10.1242/jcs.00210
  44. Cregan SP, Dawson VL, Slack RS. Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 2004;23:2785-96. https://doi.org/10.1038/sj.onc.1207517
  45. Cregan SP, Fortin A, MacLaurin JG, et al. Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J Cell Biol 2002;158:507-17. https://doi.org/10.1083/jcb.200202130
  46. Susin SA, Lorenzo HK, Zamzami N, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441-6. https://doi.org/10.1038/17135
  47. Vahsen N, Cande C, Briere JJ, et al. AIF deficiency compromises oxidative phosphorylation. EMBO J 2004;23:4679-89. https://doi.org/10.1038/sj.emboj.7600461
  48. Sharp TV, Wang HW, Koumi A, et al. K15 protein of Kaposi's sarcoma- associated herpesvirus is latently expressed and binds to HAX-1, a protein with antiapoptotic function. J Virol 2002;76:802-16. https://doi.org/10.1128/JVI.76.2.802-816.2002
  49. Chen M, Zsengeller Z, Xiao CY, Szabo C. Mitochondrial-to-nuclear translocation of apoptosis-inducing factor in cardiac myocytes during oxidant stress: potential role of poly (ADP-ribose) polymerase-1. Cardiovasc Res 2004;63:682-8. https://doi.org/10.1016/j.cardiores.2004.04.018
  50. Xiao CY, Chen M, Zsengeller Z, et al. Poly (ADP-Ribose) polymerase promotes cardiac remodeling, contractile failure, and translocation of apoptosis-inducing factor in a murine experimental model of aortic banding and heart failure. J Pharmacol Exp Ther 2005;312:891-8.
  51. Kim GT, Chun YS, Park JW, Kim MS. Role of apoptosis-inducing factor in myocardial cell death by ischemia-reperfusion. Biochem Biophys Res Commun 2003;309:619-24. https://doi.org/10.1016/j.bbrc.2003.08.045
  52. Siu PM, Bae S, Bodyak N, Rigor DL, Kang PM. Response of caspaseindependent apoptotic factors to high salt diet-induced heart failure. J Mol Cell Cardiol 2007;42:678-86. https://doi.org/10.1016/j.yjmcc.2007.01.001
  53. Choudhury S, Bae S, Kumar SR, et al. Role of AIF in cardiac apoptosis in hypertrophic cardiomyocytes from Dahl salt-sensitive rats. Cardiovasc Res 2010;85:28-37. https://doi.org/10.1093/cvr/cvp261
  54. Joza N, Susin SA, Daugas E, et al. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 2001; 410:549-54. https://doi.org/10.1038/35069004
  55. van Empel VP, Bertrand AT, van der Nagel R, et al. 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 2005;96:e92-101. https://doi.org/10.1161/01.RES.0000172081.30327.28
  56. Joza N, Oudit GY, Brown D, et al. Muscle-specific loss of apoptosisinducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy. Mol Cell Biol 2005;25:10261-72. https://doi.org/10.1128/MCB.25.23.10261-10272.2005
  57. Cheung EC, Joza N, Steenaart NA, et al. Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis. EMBO J 2006;25:4061-73. https://doi.org/10.1038/sj.emboj.7601276
  58. David KK, Sasaki M, Yu SW, Dawson TM, Dawson VL. EndoG is dispensable in embryogenesis and apoptosis. Cell Death Differ 2006; 13:1147-55. https://doi.org/10.1038/sj.cdd.4401787
  59. Irvine RA, Adachi N, Shibata DK, et al. Generation and characterization of endonuclease G null mice. Mol Cell Biol 2005;25:294-302. https://doi.org/10.1128/MCB.25.1.294-302.2005
  60. Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 2001;412:95-9. https://doi.org/10.1038/35083620
  61. Bahi N, Zhang J, Llovera M, Ballester M, Comella JX, Sanchis D. Switch from caspase-dependent to caspase-independent death during heart development: essential role of endonuclease in ischemia-induced DNA processing on differentiated cardiomyocytes. J Biol Chem 2006; 281:22943-52. https://doi.org/10.1074/jbc.M601025200
  62. Suzuki Y, Takahashi-Niki K, Akagi T, Hashikawa T, Takahashi R. Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways. Cell Death Differ 2004;11:208-16. https://doi.org/10.1038/sj.cdd.4401343
  63. Liu HR, Gao E, Hu A, et al. Role of Omi/HtrA2 in apoptotic cell death after myocardial ischemia and reperfusion. Circulation 2005;111:90-6. https://doi.org/10.1161/01.CIR.0000151613.90994.17
  64. Li Z, Zhang T, Dai H, et al. Involvement of endoplasmic reticulum stress in myocardial apoptosis of streptozocin-induced diabetic rats. J Clin Biochem Nutr 2007;41:58-67. https://doi.org/10.3164/jcbn.2007008
  65. Hamada H, Suzuki M, Yuasa S, et al. Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice. Mol Cell Biol 2004;24:8007-17. https://doi.org/10.1128/MCB.24.18.8007-8017.2004
  66. Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 2006;7:880-5. https://doi.org/10.1038/sj.embor.7400779
  67. Li J, Lee B, Lee AS. Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. J Biol Chem 2006;281:7260-70. https://doi.org/10.1074/jbc.M509868200
  68. Nickson P, Toth A, Erhardt P. PUMA is critical for neonatal cardiomyocyte apoptosis induced by endoplasmic reticulum stress. Cardiovasc Res 2007;73:48-56. https://doi.org/10.1016/j.cardiores.2006.10.001
  69. Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 2003;300:135-9. https://doi.org/10.1126/science.1081208
  70. Degterev A, Huang Z, Boyce M, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 2005;1:112-9. https://doi.org/10.1038/nchembio711
  71. Kim J, Klionsky DJ. Autophagy, cytoplasm-to-vacuole targeting pathway, and pexophagy in yeast and mammalian cells. Annu Rev Biochem 2000;69:303-42. https://doi.org/10.1146/annurev.biochem.69.1.303
  72. Gorski SM, Chittaranjan S, Pleasance ED, et al. A SAGE approach to discovery of genes involved in autophagic cell death. Curr Biol 2003; 13:358-63. https://doi.org/10.1016/S0960-9822(03)00082-4
  73. Lee CY, Baehrecke EH. Steroid regulation of autophagic programmed cell death during development. Development 2001;128:1443-55.
  74. Liang XH, Jackson S, Seaman M, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672-6. https://doi.org/10.1038/45257
  75. Berry DL, Baehrecke EH. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 2007;131: 1137-48. https://doi.org/10.1016/j.cell.2007.10.048
  76. Laugwitz KL, Moretti A, Weig HJ, et al. Blocking caspase-activated apoptosis improves contractility in failing myocardium. Hum Gene Ther 2001;12:2051-63. https://doi.org/10.1089/10430340152677403
  77. Yaoita H, Ogawa K, Maehara K, Maruyama Y. Attenuation of ischemia/ reperfusion injury in rats by a caspase inhibitor. Circulation 1998;97:276-81. https://doi.org/10.1161/01.CIR.97.3.276
  78. Okamura T, Miura T, Takemura G, et al. Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation in the ischemia- reperfused rat heart. Cardiovasc Res 2000;45:642-50. https://doi.org/10.1016/S0008-6363(99)00271-0

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