Abstract
Reperfusion after myocardial ischemia is associated with a rapid influx of calcium, leading to activation of various enzymes including calpain. Isolated perfused adult rabbit hearts subjected to global ischemia and reperfusion were studied. Calpain or a calpain-like activity was activated within 15 min after reperfusion, and preconditioning suppressed calpain activation. In contrast, caspase activation was not detected although cytochrome c was released after ischemia and reperfusion. The pro-apoptotic BH3-only Bcl-2 family member, Bid, was cleaved during ischemia/reperfusion in the adult rabbit heart. Recombinant Bid was cleaved by calpain to a fragment that was able to mediate cytochrome c release. The calpain cleavage site was mapped to a region within Bid that is extremely susceptible to proteolysis. These findings suggest that there is cross-talk between apoptotic and necrotic pathways in myocardial ischemia/reperfusion injury.
Highlights
Reperfusion after ischemia is accompanied by a rapid influx of calcium
Ischemia and reperfusion are associated with calpain activation, a finding that has been reported by many other groups
Recent interest has focused on biochemical pathways of apoptosis, and caspase activation has been reported to occur in ischemic and reperfused rat hearts [18]
Summary
Reperfusion after ischemia is accompanied by a rapid influx of calcium. Preconditioning, in which a brief period of ischemia and reperfusion confers protection against a longer episode of ischemia, preserves tissue viability through attenuation of ionic fluxes (notably protons and calcium), preservation of energy charge (less consumption of ATP), and a variety of less well characterized enzymatic alterations [1,2,3,4,5]. Caspase activation in ischemic and reperfused rat heart has been reported using an antibody that recognizes a neoepitope in activated caspase-3 [18]. In this study we report that calpain is activated shortly after ischemia/reperfusion and that preconditioning attenuates calpain activation. We demonstrate a connection between calpain and mitochondrial dysfunction mediated by Bid
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