Myocardial infarction represents a major source of morbidity and mortality, and its occurrence will continue to increase as the population ages. Cell death during myocardial ischemia and reperfusion represents both necrosis and apoptosis. Cell injury can largely be prevented by preconditioning, in which a brief period of ischemia before a more sustained ischemia protects myocardium. The mechanism of preconditioning is incompletely understood, but is associated with preservation of ATP stores, preservation of mitochondrial structure, attenuation of cytoplasmic acidification through activation of the vacuolar proton ATPase, and perhaps additional mechanisms. Cardiomyocytes surviving an ischemic insult show an upregulation of Bcl-2. Bcl-2 is located in the outer mitochondrial membrane, and both Bcl-2 and mitochondria appear to play an important role in regulating apoptosis. Using isolated cardiomyocytes from adult rabbit heart, we have shown that apoptosis is a feature of cell death due to metabolic inhibition and recovery (simulated ischemia and reperfusion). This apoptosis can be prevented with a tripeptide inhibitor of the cystine protease family that cleave at aspartic acid residues (caspase). Moreover, we find that it is possible to protect cardiomyocytes by adding the caspase inhibitor after metabolic inhibition. This observation suggests that caspase activity does not become significant until during the recovery period. We hypothesize that 1) caspases are processed from the proenzyme to the catalytically active form during ischemia (metabolic inhibition), but that 2) they do not begin to cleave substrates until the recovery phase, that 3) preconditioning prevents caspase activation or attenuates caspase activity, and 4) preconditioning preserves mitochondrial function after ischemia, and 5) preservation of mitochondrial function is related to cell survival. These hypotheses are individually testable in our model. In this application we propose to examine the kinetics of caspase activation during ischemia and reperfusion, to identify which caspases are activated, to determine the relationship between preconditioning and caspase activation, and to evaluate mitochondrial function in relation to preconditioning and recovery from metabolic inhibition.
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