Mechanisms of apoptosis after ischemia and reperfusion: Role of the renin-angiotensin system

Background: Apoptosis plays a key role in the pathogenesis of cardiac diseases. We examined the influence of the renin-angiotensin system (RAS) on different regulators of apoptosis using an isolated hemoperfused working porcine heart model of acute ischemia (2 h), followed by reperfusion (4 h). Methods and Results: 23 porcine hearts were randomized to 5 groups: hemoperfused non-infarcted hearts (C), infarcted hearts (MI: R. circumflexus), infarcted hearts treated with quinaprilat (Q), infarcted hearts treated with angiotensin-I (Ang I), and infarcted hearts treated with angiotensin-I and quinaprilat (QA). Fas, Bax, bcl-2 and p53 proteins were increased in MI hearts and further elevated by Ang I. Quinaprilat reduced Bax and p53. Bcl-2 was elevated in Q and reduced in QA. An early upregulation of caspase-3 gene and protein expression was detected in MI and Ang I hearts compared to C. Q reduced caspase-3 gene expression, but had no effect on caspase-3 and Fas protein. Conclusions: These data suggest that the RAS plays a pivotal role in cardiac apoptosis which is the early and predominant form of death in myocardial infarction. Ischemia/reperfusion induces programmed cell death via extrinsic and intrinsic pathways. Early treatment with quinaprilat attenuated cardiomyocyte apoptosis.

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