Abstract P306: Maintenance of Intracellular Zinc Homeostasis Contributes to the Mechanism by Which Postconditioning Protects the Heart from Ischemia/Reperfusion Injury

Abstract

Myocardial ischemia/reperfusion causes zinc depletion and supplementation of zinc can attenuate ischemia/reperfusion injury. The purpose of this study was to determine the role of the intracellular homeostasis in the cardioprotective mechanism of ischemic postconditioning. Isolated rat hearts were subjected to 30 min regional ischemia followed by 2 h of reperfusion. Postconditioning was elicited by six cycles of 10 second reperfusion and 10 seconds ischemia. Zinc concentration was measured with inductively coupled plasma optical spectroscopy (ICPOES). Upon reperfusion cytosolic zinc levels were dramatically decreased but this was prevented by postconditioning, indicating that postconditioning can prevent reperfusion-induced zinc loss. Moreover, postconditioning could also attenuate mitochondrial zinc loss upon reperfusion. In agreement with these observations, the anti-infarct effect of postconditioning was reversed by the zinc chelator N,N,N’,N’-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), and exogenous zinc given at reperfusion mimicked the effect of postconditioning by reducing infarct size, suggesting that intracellular zinc account for the cardioprotective effect of postconditioning. Finally, postconditioning enhanced phosphorylation of Akt, ERK, and GSK-3β upon reperfusion, and these effects of postconditioning were inhibited by TPEN, indicating that zinc may mediate the cardioprotective effect of postconditioning by activating the RISK pathway. In conclusion, these data suggest that postconditioning may protect the heart by maintaining intracellular zinc homeostasis and activation of the RISK pathway may account for zinc-mediated cardioprotection of postconditioning.