Apoptosis in cardiac myocytes - Role of the renin-angiotensin-system

  • Daniela Grimm
  • Gilbert Schönfelder
  • Martin Paul
Part of the Basic Science for the Cardiologist book series (BASC, volume 5)


Apoptosis is considered as a form of physiological cell death, characterized by chromatin condensation, cytoplasmatic blebbing and DNA fragmentation. It plays a key role during development, homeostasis, and several diseases including cardiovascular disorders. Apoptosis occurs through the activation of a cell-intrinsic suicide program. The activation of the cell suicide program is regulated by many different signals that originate from both the intracellular and extracellular milieu ( 1 ). Experimental evidence suggests that exaggerated apoptosis may account for the loss of cardiomyocytes in heart failure. Furthermore, several factors intrinsic and extrinsic to the cardiomyocytes have been suggested as potential candidates to trigger apoptosis.


Cardiac Myocytes Renin Angiotensin System Cardiomyocyte Apoptosis Myocyte Apoptosis Chronic Pressure Overload 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Steller H. Mechanisms and genes of cellular suicide. Science. 1995;267:1335–1449.CrossRefGoogle Scholar
  2. 2.
    Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994;15:7–10.PubMedCrossRefGoogle Scholar
  3. 3.
    Adams JM, Cory S. The Bcl-2 protein family: Arbiters of cell survival. Science. 1998;281:1322–1326.PubMedCrossRefGoogle Scholar
  4. 4.
    Bialik S, Geenen 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; 100:1991–1999.Google Scholar
  5. 5.
    Veinot JP, Gattinger DA, Fliss H. Early apoptosis in human myocardial infarcts. Human Pathol. 1997;28:485–492.CrossRefGoogle Scholar
  6. 6.
    Misao J, Hayakawa Y, Ohno M, Kato S, Fujiwara T, Fujiwara H. Expression of bct-2 protein, an inhibitor of apoptosis, and Bax, an accelerator of apoptosis, in ventricular myocytes of human hearts with myocardial infarction. Circulation. 1996;94:1506–1512.PubMedGoogle Scholar
  7. 7.
    Cheng W, Kajstura J, Nitahara JA, Li B, Reiss K, Liu Y, Clark WA, Krajewski S, Reed JC, Olivetti G, Anversa P. Programmed myocyte cell death affects the viable myocardium after infarction in rats. Exp Cell Res. 1996;226:316–327.PubMedCrossRefGoogle Scholar
  8. 8.
    Chen C, Ma I, Linfert DR, Lai T, Fallon JT, Gillam LD, Waters DD, Tsongalis GJ. Myocardial cell death and apoptosis in hibernating myocardium. J Am Coll Cardiol. 1997; 30:1407–1412.PubMedCrossRefGoogle Scholar
  9. 9.
    Anversa P, Cheng W, Liu Y, Leri A, Redaelli G, Kajstura J. Apoptosis and myocardial infarction. Basic Res Cardiol. 1998;93:Suppl3:8–12.PubMedCrossRefGoogle Scholar
  10. 10.
    Kajsura 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 infarctsize in rats. Lab Invest. 1996;74:86–107.Google Scholar
  11. 11.
    Olivetti G, Capasso JM, Sonnenblick EH, Anversa P. Side-to-side slippage of myocytes in ventricular wall remodeling acutely after myocardial infarction in rats. Circ Res. 1990;67:23–34.PubMedGoogle Scholar
  12. 12.
    Grimm D, Kromer EP, Böcker W, Bruckschlegel G, Holmer SR, Riegger GAJ, Schunkert H. Regulation of extracellular matrix proteins in pressure-overload cardiac hypertrophy: effects of angiotensin-converting enzyme inhibition. J Hyper tens. 1998;1345–1355.Google Scholar
  13. 13.
    Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation. 1991;83:1849–1865.PubMedGoogle Scholar
  14. 14.
    Bing OHL. Hypothesis: apoptosis may be a mechanism for the transition to heart failure with chronic pressure overload. J Mol Cell Cardiol. 1994;26:943–948.PubMedCrossRefGoogle Scholar
  15. 15.
    Ross J, Sonnenblick EH, Taylor HM, Covell JW. Diastolic geometry and sarcomeric lengths in the chronically dilated left ventricle. Circ Res. 1971;28:49–61.PubMedGoogle Scholar
  16. 16.
    Vitali-Mazza L, Anversa P, Tedeschi F, Mastandrea R, Mavilla V, Visioli O. Ultrastructural basis of acute left ventricular failure from severe acute aortic stenosis in the rabbit. J Mol Cell Cardiol. 1972; 4:661–671.PubMedCrossRefGoogle Scholar
  17. 17.
    Komuro I., Kaida T, Shibazaki Y, Kurabayashi M, Katoh Y, Hoh E, Takaku F, Yazaki Y. Stretching cardiac myocytes stimulates protooncogene expression. J Biol Chem. 1990; 265: 3595–3598.PubMedGoogle Scholar
  18. 18.
    Schneider MD, Roberts R, Parker TG. Modulation of cardiac genes by mechanical stress. The oncogene signaling hypothesis. Mol Biol Med. 1991; 8: 167–183.PubMedGoogle Scholar
  19. 19.
    Sadoshima J, Jahn L, Takashashi T, Kulik TJ, Izumo S. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy. J. Biol. Chem. 1992, 267:10551–10660PubMedGoogle Scholar
  20. 20.
    Sadoshima J, Takahashi T, Jahn L, Izumo S. Roles of mechano-sensitive ion channels, cytoskeleton, and contractile activity in stretch-induced immediate-early gene expression and hypertrophy of cardiac myocytes. Proc Natl Acad Sc. USA. 1992;89: 9905–9909.CrossRefGoogle Scholar
  21. 21.
    Sadoshima J, Izumo S. Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO. (Eur. Mol. Biol. Organ.). 1993;2:1681–1692.Google Scholar
  22. 22.
    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;96:2247–2259.PubMedGoogle Scholar
  23. 23.
    Cigola E, Kaijstura J, Li B, Meggs LG, Anversa P. Angiotensin II activates programmed cell death in vitro. Exp Cell Res. 1997;231:363–371.PubMedCrossRefGoogle Scholar
  24. 24.
    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;29:859–870.PubMedCrossRefGoogle Scholar
  25. 25.
    Miyashita T, Reed J. Tumor suppressor p53 is a direct transcriptional activator of the human Bax gene. Cell. 1995; 80: 293–299.PubMedCrossRefGoogle Scholar
  26. 26.
    Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the Bcl-2 gene. Cancer Res. 1994;54: 3131–3135.PubMedGoogle Scholar
  27. 27.
    Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ. Bcl-2 deficient mice demonstrated fulminant lymphoid apoptosis, polycystic kidneys and hypopigmented hair. Cell. 1993;75:229–240.PubMedCrossRefGoogle Scholar
  28. 28.
    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. Celt Res. 1997;234: 57–65.CrossRefGoogle Scholar
  29. 29.
    Leri A, Claudio PP, Li Q, Wang X, Reiss K, Wang S, Malhotra A, Kajstura J, Anversa P. Stretch-mediated release of Angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to Bax protein ratio in the cell. J Clin Invest. 1998;101:1326–1342.PubMedGoogle Scholar
  30. 30.
    Oltvai ZN, Korsmeyer SJ. Checkpoints of dueling dimers foil death wishes. Cell. 1994; 79:189–192.PubMedCrossRefGoogle Scholar
  31. 31.
    Hamet P, Richard L, Dam TV, Teiger E, Orlov SN, Gaboury L, Gossard F, Tremblay J. apoptosis in target organs in hypertension. Hypertension. 1995;26:642–648.PubMedGoogle Scholar
  32. 32.
    Diez J, Panizo A, Hernandez M, Vega F, Sola I, Fortuno MA, Pardo J. Cardiomyocyte apoptosis and cardiac angiotensin-converting enzyme in spontaneously hypertensive rats. Hypertension. 1997;30:1029–1034.PubMedGoogle Scholar
  33. 33.
    Li Z, Bing OHL, Long X, Robinson KG, Lakatta EG. Increased cardiomyocye apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Physiol. 1997;272:H2313–H2319.PubMedGoogle Scholar
  34. 34.
    Fortuno MA, Ravassa S, Etayo JC, Diez J. Overexpression of Bax protein and enhanced apoptosis in the left ventricle of spontaneously hypertensive rats. Effects of AT blockade with losartan. Hypertension. 1998;32:280–286.PubMedGoogle Scholar
  35. 35.
    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;148:141–149.PubMedGoogle Scholar
  36. 36.
    Goussev A, Sharov VG, Shimoyama H, Tanimura M, Lesch M, Goldstein S, Sabbah HN. Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure. Am J Physiol. 1998;275:H626–631.PubMedGoogle Scholar
  37. 37.
    Ruffolo RR Jr. Feuerstein GZ. Neurohormonal activation, oxygen free radicals, and apoptosis in the pathogenesis of congestive heart failure. J Cardiovasc Pharmacol 1998;32Suppl 1:S22–30.PubMedGoogle Scholar
  38. 38.
    Yue TL, Ma XL, Wang X, Romanic AM, Liu GL, Louden C, Gu JL, Kumar S, Poste G, Ruffolo RR Jr. Feuerstein GZ. Possible involvement of stress-activated protein kinase signaling pathway and Fas receptor expression in prevention of ischemia/reperfusion-induced cardiomyocyte apoptosis by carvedilol. Circ Res. 1998;82:166–174.PubMedGoogle Scholar
  39. 39.
    Olivetti G, Abbi R, Quaini F, Kajstura J Cheng W, Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewski S, Reed JC, Anversa P. Apoptosis in the failing heart. N Engl J Med, 1997;336:1131–1141.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Daniela Grimm
    • 1
  • Gilbert Schönfelder
    • 1
  • Martin Paul
    • 1
  1. 1.Freie Universität BerlinBerlinGermany

Personalised recommendations