Abstract
Apoptosis or programmed cell death is an important physiologic event crucial for the selective removal of damaged or unwanted cells from body tissues. In the cardiovascular system, apoptosis has been observed in the vasculature and myocardium. Untimely or inappropriate myocardial cell loss through an apoptotic process may contribute to ventricular remodeling and the ultimate demise of ventricular function following injury. Therapeutic interventions designed to modulate or prevent myocardial apoptotic cell loss may therefore prove beneficial in maintaining cardiac function. Incite into the molecular mechanisms that govern apoptosis in mammalian cells has led to the identification of several key factors that promote or prevent the apoptotic process. In this report, we discuss putative regulators of cardiac cell apoptosis with specific reference to the tumor suppressor proteins, p53 and Rb. The interplay between these factors, as well as the anti-apoptotic molecules related to the Bcl-2 the family are discussed in the context of the heart under normal and disease conditions.
Similar content being viewed by others
References
Wyllie AH. Apoptosis and the regulation of cell numbers in normal and neoplastic tissues: an overview. Cancer Metastasis Rev 1992; 11: 95-103.
Wyllie AH. Death from inside out: an overview. Philos Trans R Soc Lond B Biol Sci 1994; 345: 237-241.
Martin SJ, Green DR. Apoptosis and cancer: the failure of controls on cell death and cell survival. Crit Rev Oncol Hematol 1995; 18: 137-153.
Cohen JJ. Apoptosis. Immunol Today 1993; 14: 126-130.
Cohen JJ. Apoptosis: physiologic cell death. J Lab Clin Med 1994; 124: 761-765.
Schwartzman RA, Cidlowski JA. Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocr Rev 1993; 14: 133-151.
Cotter TG, al Rubeai M. Cell death (apoptosis) in cell culture systems. Trends Biotechnol 1995; 13: 150-155.
Perry G, Nunomura A. Apoptosis and Alzheimer's disease (letter). Science 1998; 282: 1268-1269.
Terai C, Kornbluth RS, Pauza CD, Richman DD, Carson DA. Apoptosis as a mechanism of cell death in cultured T lymphoblasts acutely infected with HIV-1. J Clin Invest 1991; 87: 1710-1715.
Hackam AS, Singaraja R, Wellington CL, Metzler M, McCutcheon K, Zhang T, Kalchman M, Hayden MR. The influence of huntingtin protein size on nuclear localization and cellular toxicity. J Cell Biol 1998; 141: 1097-1105.
Haber DA. Telomeres, cancer, and immortality. N Engl J Med 1995; 332: 955-956.
Yonish Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 1991; 352: 345-347.
Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T, Hovig E, Smith-Sorensen B, Montesano R, Harris CC. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res 1994; 22: 3551-3555.
Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA, Jr, Butel JS, Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 1992; 356: 215-221.
White E. Death-defying acts: a meeting review on apoptosis. Genes Dev 1993; 7: 2277-2284.
Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes [see comments]. Nature 1993; 362: 847-849.
Yonish Rouach E, Grunwald D, Wilder S, Kimchi A, May E, Lawrence JJ, May P, Oren M. p53-mediated cell death: relationship to cell cycle control. Mol Cell Biol 1993; 13: 1415-1423.
Kirshenbaum LA, de Moissac D. The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation 1997; 96: 1580-1585.
Long X, Crow MT, Sollott SJ, O'Neill L, Menees DS, de Lourdes Hipolito M, Boluyt MO, Asai T, Lakatta EG. Enhanced expression of p53 and apoptosis induced by blockade of the vacuolar proton ATPase in cardiomyocytes. J Clin Invest 1998; 101: 1453-1461.
Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 1994; 8: 9-22.
Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X, Ferrara P, McKeon F, Caput D. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 1997; 90: 809-819.
Jost CA, Marin MC, Kaelin WG, Jr. p73 is a human p53-related protein that can induce apoptosis (see comments). Nature 1997; 389: 191-194.
Marin MC, Jost CA, Irwin MS, DeCaprio JA, Caput D, Kaelin WG, Jr. Viral oncoproteins discriminate between p53 and the p53 homolog p73. Mol Cell Biol 1998; 18: 6316-6324.
Prives C. How loops, beta sheets, and alpha helices help us to understand p53. Cell 1994; 78: 543-546.
Prives C, Bargonetti J, Farmer G, Ferrari E, Friedlander P, Wang Y, Jayaraman L, Pavletich N, Hubscher U. DNA-binding properties of the p53 tumor suppressor protein. Cold Spring Harb Symp Quant Biol 1994; 59: 207-213.
el Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 1994; 54: 1169-1174.
Perry ME, Levine AJ. P53 and mdm-2: interactions between tumor suppressor gene and oncogene products. Mt Sinai J Med 1994; 61: 291-299.
Hedborg F, Ohlsson R, Sandstedt B, Grimelius L, Hoehner JC, Pahlman S. IGF2 expression is a marker for paraganglionic/SIF cell differentiation in neuroblastoma. Am J Pathol 1995; 146: 833-847.
Buckbinder L, Talbott R, Velasco Miguel S, Takenaka I, Faha B, Seizinger BR, Kley N. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 1995; 377: 646-649.
Pierzchalski P, Reiss K, Cheng W, Cirielli C, Kajstura J, Nitahara JA, Rizk M, Capogrossi MC, Anversa P. p53 Induces myocyte apoptosis via the activation of the renin-angiotensin system. Exp Cell Res 1997; 234: 57-65.
Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995; 80: 293-299.
Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol 1994; 124: 1-6.
Korsmeyer SJ. Regulators of cell death. Trends Genet 1995; 11: 101-105.
Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998; 281: 1322-1326.
Korsmeyer SJ. Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. Annu Rev Immunol 1992; 10: 785-807.
Agocha A, Lee HW, Eghbali-Webb M. Hypoxia regulates basal and induced DNA synthesis and collagen type I production in human cardiac fibroblasts: effects of transforming growth factor-beta1, thyroid hormone, angiotensin II and basic fibroblast growth factor. J Mol Cell Cardiol 1997; 29: 2233-2244.
Yin XM, Oltvai ZN, Korsmeyer SJ. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax (see comments). Nature 1994; 369: 321-323.
Tanaka S, Saito K, Reed JC. Structure-function analysis of the Bcl-2 oncoprotein. Addition of a heterologous transmembrane domain to portions of the Bcl-2 beta protein restores function as a regulator of cell survival. J Biol Chem 1993; 268: 10920-10926.
Yin XM, Oltvai ZN, Korsmeyer SJ. Heterodimerization with Bax is required for Bcl-2 to repress cell death. Curr Top Microbiol Immunol 1995; 194: 331-338.
Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN. Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol 1993; 4: 327-332.
Petit PX, Goubern M, Diolez P, Susin SA, Zamzami N, Kroemer G. Disruption of the outer mitochondrial membrane as a result of large amplitude swelling: the impact of irreversible permeability transition. FEBS Lett 1998; 426: 111-116.
Zamzami N, Marchetti P, Castedo M, Zanin C, Vayssiere JL, Petit PX, Kroemer G. Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J Exp Med 1995; 181: 1661-1672.
Macdonald G, Shi L, Velde CV, Lieberman J, Greenberg AH. Mitochondria-dependent and-independent regulation of granzyme B-induced apoptosis (in process citation). J Exp Med 1999; 189: 131-144.
Bossy-Wetzel E, Newmeyer DD, Green DR. Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 1998; 17: 37-49.
Huang DC, Adams JM, Cory S. The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4. EMBO J 1998; 17: 1029-1039.
Pan G, O'Rourke K, Dixit VM. Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex. J Biol Chem 1998; 273: 5841-5845.
Hu Y, Benedict MA, Wu D, Inohara N, Nunez G. Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc Natl Acad Sci USA 1998; 95: 4386-4391.
Sardet C, Vidal M, Cobrinik D, Geng Y, Onufryk C, Chen A, Weinberg RA. E2F-4 and E2F-5, two members of the E2F family, are expressed in the early phases of the cell cycle. Proc Natl Acad Sci USA 1995; 92: 2403-2407.
Strom DK, Cleveland JL, Chellappan S, Nip J, Hiebert SW. E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation. Cell Growth Differ 1998; 9: 59-69.
Hijmans EM, Voorhoeve PM, Beijersbergen RL, van't Veer LJ, Bernards R. E2F-5, a new E2F family member that interacts with p130 in vivo. Mol Cell Biol 1995; 15: 3082-3089.
Benedict WF, Murphree AL, Banerjee A, Spina CA, Sparkes MC, Sparkes RS. Patient with 13 chromosome deletion: evidence that the retinoblastoma gene is a recessive cancer gene. Science 1983; 219: 973-975.
Hsieh TC, Xu W, Chiao JW. Growth regulation and cellular changes during differentiation of human prostatic cancer LNCaP cells as induced by T lymphocyte-conditioned medium. Exp Cell Res 1995; 218: 137-143.
Hamel PA, Phillips RA, Muncaster M, Gallie BL. Speculations on the roles of RB1 in tissue-specific differentiation, tumor initiation, and tumor progression. FASEB J 1993; 7: 846-854.
Venter DJ, Bevan KL, Ludwig RL, Riley TE, Jat PS, Thomas DG, Noble MD. Retinoblastoma gene deletions in human glioblastomas. Oncogene 1991; 6: 445-448.
Lee EY, To H, Shew JY, Bookstein R, Scully P, Lee WH. Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science 1988; 241: 218-221.
Horowitz JM, Park SH, Bogenmann E, Cheng JC, Yandell DW, Kaye FJ, Minna JD, Dryja TP, Weinberg RA. Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci USA 1990; 87: 2775-2779.
Weinberg RA. The molecular basis of oncogenes and tumor suppressor genes. Ann NY Acad Sci 1995; 758: 331-338.
Mymryk JS, Shire K, Bayley ST. Induction of apoptosis by adenovirus type 5 E1A in rat cells requires a proliferation block. Oncogene 1994; 9: 1187-1193.
Lowe SW, Ruley HE. Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev 1993; 7: 535-545.
Debbas M, White E. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev 1993; 7: 546-554.
Kirshenbaum LA, Schneider MD. Adenovirus E1A represses cardiac gene transcription and reactivates DNA synthesis in ventricular myocytes, via alternative pocket protein-and p300-binding domains. J Biol Chem 1995; 270: 7791-7794.
Moran E, Zerler B, Harrison TM, Mathews MB. Identification of separate domains in the adenovirus E1A gene for immortalization activity and the activation of virus early genes. Mol Cell Biol 1986; 6: 3470-3480.
Kirshenbaum LA, Abdellatif M, Chakraborty S, Schneider MD. Human E2F-1 reactivates cell-cycle progreesion in ventricular myocytes and represses cardiac gene transcription. Developmental Biology 1996; 179: 402-411.
Dobrowolski SF, Stacey DW, Harter ML, Stine JT, Hiebert SW. An E2F dominant negative mutant blocks E1A induced cell cycle progression. Oncogene 1994; 9: 2605-2612.
Suda K, Holmberg EG, Nornes HO, Neuman T. DNA synthesis is induced in adult neurons after expression of E2F1 and E1A. Neuroreport 1994; 5: 1749-1751.
Kowalik TF, DeGregori J, Schwarz JK, Nevins JR. E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. J Virol 1995; 69: 2491-2500.
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: 426-433.
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: 2635-2643.
Fliss H, Gattinger D. Apoptosis in ischemic and reperfused rat myocardium. Circ Res 1996; 79: 949-956.
Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 1994; 94: 1621-1628.
Gottlieb RA, Gruol DL, Zhu JY, Engler RL. Preconditioning rabbit cardiomyocytes: role of pH, vacuolar proton ATPase, and apoptosis. J Clin Invest 1996; 97: 2391-2398.
Yaoita H, Ogawa K, Maehara K, Maruyama Y. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor (see comments). Circulation 1998; 97: 276-281.
Kajstura J, Cheng W, Reiss K, Clark WAR, Sonnenblick EH, Krajewski S, Reed JC, Anversa P. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infartc size in rats. Laboratory Investigation 1996; 74: 86-107.
Li P, Hofmann PA, Li B, Malhotra A, Cheng W, Sonnenblick EH, Meggs LG, Anversa P. Myocardial infarction alters myofilament calcium sensitivity and mechanical behavior of myocytes. Am J Physiol 1997; 272: H360-70.
Akiyama K, Gluckman TL, Terhakopian A, Jinadasa PM, Narayan S, Singaswamy S, Massey B, 3rd, Bing RJ. Apoptosis in experimental myocardial infarction in situ and in the perfused heart in vitro. Tissue Cell 1997; 29: 733-743.
Narula J, Kharbanda S, Khaw BA. Apoptosis and the heart. Chest 1997; 112: 1358-1362.
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 (see comments). N Engl J Med 1996; 335: 1182-1189.
James TN. Normal and abnormal consequences of apoptosis in the human heart. From postnatal morphogenesis to paroxysmal arrhythmias. Circulation 1994; 90: 556-573.
Sabbah HN, Sharov VG, Goldstein S. Programmed cell death in the progression of heart failure. Ann Med 1998; 30(Suppl 1): 33-38.
Isner JM, Kearney M, Bortman S, Passeri J. Apoptosis in human atherosclerosis and restenosis. Circulation 1995; 91: 2703-2711.
Kajstura J, Mansukhani M, Cheng W, Reiss K, Krajewski S, Reed JC, Quaini F, Sonnenblick EH, Anversa P. Programmed cell death and expression of the protooncogene bcl-2 in myocytes during postnatal maturation of the heart. Exp Cell Res 1995; 219: 110-121.
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: 2722-2728.
Bialik S, Green DL, Sasson IE, Cheng R, Horner 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: 1363-1372.
Ehinger M, Bergh G, Johnsson E, Baldetorp B, Olsson I, Gullberg U. p53-dependent and-independent differentiation of leukemic U-937 cells: relationship to cell cycle control. Exp Hematol 1998; 26: 1043-1052.
McDonald AC, Brown R. Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors. Br J Cancer 1998; 78: 745-751.
Chandler JM, Alnemri ES, Cohen GM, MacFarlane M. Activation of CPP32 and Mch3 alpha in wild-type p53-induced apoptosis. Biochem J 1997; 322: 19-23.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Regula, K., Kirshenbaum, L.A. Apoptosis in ventricular myocytes: the role of tumor suppressor proteins. Apoptosis 4, 229–234 (1999). https://doi.org/10.1023/A:1009640124029
Issue Date:
DOI: https://doi.org/10.1023/A:1009640124029