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Apoptosis in the heart: when and why?

  • Part II: Cardiac Hypertrophy and Failure
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Abstract

Since mammalian cardiac myocytes essentially rely on aerobic energy metabolism, it has been assumed that cardiocytes die in a catastrophic breakdown of cellular homeostasis (i.e. necrosis), if oxygen supply remains below a critical limit. Recent observations, however, indicate that a process of gene-directed cellular suicide (i.e. apoptosis) is activated in terminally differentiated cardiocytes of the adult mammalian heart by ischemia and reperfusion, and by cardiac overload as well. Apoptosis or programmed cell death is an actively regulated process of cellular self destruction, which requires energy and de novo gene expression, and which is directed by an inborn genetic program. The final result of this program is the fragmentation of nuclear DNA into typical “nucleosomal ladders”, while the functional integrity of the cell membrane and of other cellular organelles is still maintained. The critical step in this regulated apoptotic DNA fragmentation is the proteolytic inactivation of poly-[ADPribose]-polymerase (PARP) by a group of cysteine proteases with some structural homologies to interleukin-1β-converting enzyme (ICE-related proteases [IRPs] such as apopain, yama and others). PARP catalyzes the ADP-ribosylation of nuclear proteins at the sites of spontaneous DNA strand breaks and thereby facilitates the repair of this DNA damage. IRP-mediated destruction of PARP, the ‘supervisor of the genome’, can be induced by activation of membrane receptors (e.g. FAS or APOI) and other signals, and is inhibited by activation of ‘anti-death genes’ (e.g. bcl-2). Overload-triggered myocyte apoptosis appears to contribute to the transition to cardiac failure, which can be prevented by therapeutic hemodynamic unloading. In myocardial ischemia, the activation of the apoptotic program in cardiocytes does not exclude their final destiny to catastrophic necrosis with release of cytosolic enzymes, but might be considered as an adaptive process in hypoperfused ventricular zones, sacrificing some jeopardized myocytes to regulated apoptosis, which may by less arrhythmogenic than necrosis with the primary disturbance of membrane function.

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    Hans Jürgen Brömme & Jürgen Holtz

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Jürgen Brömme, H., Holtz, J. Apoptosis in the heart: when and why?. Mol Cell Biochem 163, 261–275 (1996). https://doi.org/10.1007/BF00408667

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