New opportunities for heart disease therapeutics

  • Giora Z. Feuerstein
Part of the Basic Science for the Cardiologist book series (BASC, volume 5)


Apoptosis was first introduced into biology in a seminal paper by a group of pathologists studying cell population regulation (1). In this paper, the authors described a form of cell death marked by its singularity, a unique morphology and resolution without apparent “traces” (e.g., inflammation) in the tissue of origin. These features of cell death were contrasted to various forms of cell death by necrosis, due to noxious stimuli leading to cell membrane disruption, swelling, disintegration, cell-content leakage and local inflammation. Featuring prominently in the apoptotic process are the “apoptotic bodies” (fragments of dense DNA surrounded by an apparently intact plasma membrane), DNA condensation and fragmentation (the latter noted as “ladder” when separated on DNA-gel electrophoresis). The apoptosis phenotype has been later on associated with “programmed cell death” (PCD) described first in the nematode, C. elegance, where genetically specified deletions of cells during development followed a highly timed activation of specific genes (ced-3/4) (2). It is now quite common to use apoptosis and PCD interchangeably; in this review, apoptosis represents the cellular phenotype resulting from activation of genomic programs that lead to DNA damage and cell death. The objectives of this review are: a. to highlight the key evidence on apoptosis in human cardiac myocytes; b. review the key stimuli and signal transduction pathways identified in cardiac myocytes; c. discuss the significance of apoptosis in cardiac function and disease; d. suggest potential novel therapeutic strategies for cardiac diseases based on modulation of selected molecular targets in cardiomyocyte apoptosis.


Cardiac Myocytes Cardiac Remodel Cardiomyocyte Apoptosis Heart Failure Condition Cardiac Myocyte Apoptosis 
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.
    Kerr JFR, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239–257.PubMedGoogle Scholar
  2. 2.
    Yuan, J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-lβ-converting enzyme. Cell 1993; 75: 641–652.PubMedCrossRefGoogle Scholar
  3. 3.
    Anversa P, Leri A, Behrami CA, Guerra S, Kajstura J. Myocyte death and growth in failing heart. Lab Invest 1998; 78: 767–786.PubMedGoogle Scholar
  4. 4.
    Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA. Apoptosis in myocytes in end-stage heart failure. New Engl J Med 1996; 335: 1182–1189.PubMedCrossRefGoogle Scholar
  5. 5.
    Haunstetter A, Izumo S. Apoptosis. Basic mechanisms and implications for cardiovascular disease. Circ Res 1998; 82: 1111–1129.PubMedGoogle Scholar
  6. 6.
    Yaoita H, Ogawa K, MaeLare K, Maruyama Y. Attenuation of ischemia/repercussion injury in rats by a caspase inhibitor. Circulation 1998; 97: 276–281.PubMedGoogle Scholar
  7. 7.
    Yue T-L, Wang X-K, Romanic Am, Liu G-L, Louden C, Gu J-L, Kumai 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 bycarvedilol. Circ Res 1998; 82: 166–174.PubMedGoogle Scholar
  8. 8.
    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 AT1 blockade with losartan. Hypertension1998; 32:280–286.PubMedGoogle Scholar
  9. 9.
    Salvesen GS, Dixit VM. Caspases: intraceltular signaling by proteolysis. Cell 1997:91: 443–446.PubMedCrossRefGoogle Scholar
  10. 10.
    Black SC, Huang JQ, Rezaiefar P, Rodinovic S, Eberhardt A, Nicholson DW, Rodger IW. Co-Localization of the cystein protease caspase-3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in rats. J Mol Cell Cardiol 1998; 30: 733–742.PubMedCrossRefGoogle Scholar
  11. 11.
    Adams JW, Sokata Y, Davis MG, Sali V, Wang Y, Liggett SB, Chien KR, Brown JH, Dom GW. Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apopotic heart failure. Proc Natl Acad Sci 1998; 95: 10140–10145.PubMedCrossRefGoogle Scholar
  12. 12.
    Hofmann K, Dixit VM. Ceramide in apoptosis-does it really matter? Trends in Biochem Science. 1998;374–377.Google Scholar
  13. 13.
    Kirshenbaum LA, Moissac D, The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation 1997; 96: 1580–1585PubMedGoogle Scholar
  14. 14.
    Hirota H, Chen J, Betz UAK, Rajewsky TK, Gu Y, Ross J, Muller W, Chien KA. Loss of a 8PB30 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomedrinical stress. Cell 97: 189–1981999PubMedCrossRefGoogle Scholar
  15. 15.
    Kitogawa K, Matsumoto M, Tsujimoto Y, Ohtsuki T, Kuwabara K, Matsushita K, Yang G, Tanabe H, Martinou J-C, Hori M, Yanagibara T. Amelioration of hippocampal neuronal damage after global ischemia by neuronal over expression of bcl-2 in transgenic mice. Stroke 29; 2616–2621, 1998.Google Scholar
  16. 16.
    Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, Blumenthal MJ, Heys JR, Landvatter SW, Strickler SM, McLaughlin MM, Siemens IR, Fisher SM, Livi GP, White JR, Adams JL, Young PR. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 1994; 372: 739–746.PubMedCrossRefGoogle Scholar
  17. 17.
    Ma X-L, Kumar S, Gao F, Louden C, Lopez BL, Christopher TA, Wang C, Lee JC, Feuerstein G, Yue T-L. Inhibition of p38 mitogen activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation 99; 1685–1691, 1999.PubMedGoogle Scholar
  18. 18.
    Yue T-L, Wang C, Romanic AM, Kikly K, Keller P, De Wolf WE, Hart TK, Thomas HC, Storer B, Gu J-L, Wang XK, Feuerstein G. Staurosporine-induced apoptosis in cardiomyocytes: a potential role of caspase 3. J. Mol Cell Cardiol 30; 495–507 1998.PubMedCrossRefGoogle Scholar
  19. 19.
    Feuerstein GZ, Shusterman NH, Ruffolo RR Jr. Carvedilol Update IV: prevention of oxidative stress and cardiac remodeling in heart failure progression. Drug of today 1997; 33: 453–473.Google Scholar
  20. 20.
    Packer M, Colucci WS, Sackner-Bernstein J, Liang C-S, Goldscher DA, Freeman I, Kukin ML, Kinhal V, Udelson JE, Klapholz M, Gottlieb SS, Pearle D, Cody RJ, Gregory JJ, Kantrowitz NE, LeJemtel TH, Young ST, Lukas MA, Shusterman NH. Double blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE trial. Circulation 1996; 94: 2793–2799.PubMedGoogle Scholar
  21. 21.
    Australia/New Zealand Heart Failure Collaborative Group. Randomized, placebo controlled trial of carvedilol in patients with congestive heart failure due to ischemic heart disease. Lancet 1997; 349:375–380.CrossRefGoogle Scholar
  22. 22.
    Wang L, Ma W, Markovich R, Chen J-W, Wang PH. Regulation of cardiomyocyte apoptotic signaling by Insulin-like growth Factor 1. Circ Res 1998; 83: 516–522.PubMedGoogle Scholar
  23. 23.
    Okubo Y, Blakesley VA, Stannard B, Gutkind S, LeRoith D. Insulin-like growth factor-I inhibits the stress-activated protein kinase-Jun N-terminal kinase. J Biol Chem 1998; 273: 25961–25966.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Giora Z. Feuerstein
    • 1
  1. 1.DuPont Pharmaceuticals CorporationWilmingtonUSA

Personalised recommendations