A Definition poptosis, or programmed cell death, is an energy-dependent process that effects the controlled removal of a cell. The process is present during normal myocyte development and is activated in response to cell injury and results in the removal of the injured cell without damaging surrounding tissue.
Apoptotic cell death follows well-defined time-depend-ent processes, which result in changes in the plasma membrane, proteolysis of intracellular proteins, loss of mitochondrial function, and characteristic DNA cleavage. The morphologic changes seen in apoptosis include cell shrinkage, loss of cell-cell contacts, membrane blebbing, and nuclear condensation, terminating in the breakdown of the cell into apoptotic bodies that are phagocytosed by surrounding cells.
Unlike cell necrosis, apoptosis does not elicit an inflammatory response, and plasma membrane integrity is maintained until late in the process. The preservation of membrane integrity limits local tissue damage by preventing the leakage of noxious intracellular contents into the interstitium. This is an important feature of apoptotic cell death/removal that occurs during development and cellular injury.
Apoptotic cardiomyocyte death is an increasingly recognized feature of congestive heart failure and acute myocardial infarction.
The apoptotic machinery
Apoptosis is a tightly regulated and evolutionarily conserved process. A group of cell death (CED) genes have been identified as playing a central role. The caspases (cysteine-containing aspartate-specific proteases) are instrumental in the execution of apoptosis; the Bcl-2 proteins can be either pro- or antiapoptotic and are seen as arbiters of cell survival.
Caspases are proapoptotic and exist as proenzymes that are activated by cleavage at specific protein sequences. Following activation, they have proteolytic activity and cleave specific substrates. Caspases activated early in the process (initiators) act on downstream caspases (effectors) in a caspase cascade via feedback amplification. Ultimately, the caspase cascade leads to the cleavage of target intracellular proteins resulting in their activation or degradation. In this way, caspases recruit and activate proteins involved in the apoptotic process (eg, caspase-dependent endonuclease), inactivate survival proteins (eg, the extracellularly responsive kinases and the DNA repair enzyme poly-ADP-ribosyl polymerase), and act directly on cytoskeletal proteins, resulting in plasma membrane changes.
The Bcl-2 proteins influence cell survival primarily by controlling the mitochondrial response to apoptotic signals, although direct inhibition of caspase activity may occur. Activation of the mitochondrial apoptotic process is regarded as the point of no return in apoptosis. Mitochondrial involvement in apoptosis is evidenced by the loss of the mitochondrial membrane, opening of mitochondrial transition pores, disruption of the electron transport chain, generation of reactive oxygen species, and translocation of cytochrome cto the cytoplasm, where it activates caspases. Proapoptotic Bcl-2 proteins contribute to this process by disrupting the function of the mitochondrial membranes and their associated proteins. Cardiac myocyte apoptosis may be induced by tumor necrosis factor-a, oxidative stress, atrial natriuretic peptide, hypoxia, and stretching.
Apoptosis occurs in the infarcted area, border zone, and distal myocardium in acute myocardial infarction. Thrombolysis provides another means of inducing apoptotic cell death in cardiac myocytes; oxidative stress that occurs during reperfusion injury has been shown to induce apoptosis, over and above that induced by ischemia. The degree of apoptotic cell death following ischemia/reperfusion may be reduced by the use of caspase inhibitors, antioxidants, and ischemic preconditioning.
Heart failure is characterized by a significant increase in apoptotic myocyte death in spite of the enhanced expression of antiapoptotic gene products in the cells. The presence of programmed cell death in the pathologic heart is interpreted as a contributory factor in the evolution to end-stage disease. However, questions remain as to whether apoptosis is a critical event in the transition from compensated to decompensated cardiac hypertrophy and the onset of ventricular dysfunction.
Ventricular dilatation has been recognized as an accurate predictor of heart failure; cavity dilatation correlates with deterioration of cardiac pump function and poor survival in the myopathic heart. This anatomic condition is characterized by diastolic overloading, sarcomere stretching, apoptotic cell death, and side-to-side slippage of myocytes within the wall. Translocation of myocytes may account for most mural thinning and ventricular dilatation as a result of an acute increase in filling pressure. Importantly, overstretching of the myocardium in vitro is coupled with activation of apoptosis, myocyte slippage, and impaired active and passive tensions, strongly suggesting that programmed cell death is implicated in the architectural rearrangement of myocytes, ventricular dilatation, and decreased force development of the stressed myocardium in vivo.
It is noteworthy to emphasize that myocyte slippage and the consequent reduction in wall thickness and mural
Number of myocytes occur in the absence of collagen accumulation in the myocardium. This phenomenon raises the possibility that necrotic myocyte cell death is a minor component of wall restructuring and that apoptosis is the primary event responsible for the acute expansion in cavity volume. Moreover, ventricular dilatation in the decompensated heart is an ongoing process and sudden elevations in diastolic pressure and wall stress may trigger further apoptosis, promoting additional increases in ventricular size. It is generally believed that chamber dilatation following a large myocardial infarct, volume overload, or cardiomyopathy represents a compensatory anatomic modification that allows the heart to maintain stroke volume at the expense of an increased end-diastolic volume. However, the increase in diastolic cardiac dimension is not restricted to sarcomere elongation and the increase in chamber volume mediated by the Frank-Star-ling mechanism, but involves cell death and mural slippage of myocytes. This may be regarded as a pathologic form of ventricular dilatation whose magnitude exceeds the physiologic levels associated with sarcomere stretching. Myocyte apoptosis and wall restructuring may create an irreversible state in the myocardium, comprising chronic dilatation and the continuing deterioration of cardiac hemodynamics with time.
Although the case has been made that programmed myocyte cell death may be a critical variable in the initiation and progression of ventricular dilatation in the overloaded heart, the actual influence of apoptosis in the genesis and evolution of cardiac failure remains to be determined.
Therapeutic intervention to reduce cardiomyocyte loss through programmed cell death could salvage viable myocardium in both myocardial infarction and congestive heart failure. To an extent, this may already be incorporated in clinical practice thanks to angiotensin-converting enzyme inhibitors and antioxidants, notably carvedilol.
Anversa P. Myocyte apoptosis and heart failure. Eur Heart J. Cook SA, Poole-Wilson PA. Cardiac myocyte apoptosis. Eur Heart J. 1998;19:359-360. 1999;20:1619-1629.
pathophysiology; cardiomyocyte; apoptosis; myocardial infarction
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