Cardioprotective effect of zinc requires ErbB2 and Akt during hypoxia/reoxygenation

Recent literature suggests that exogenous zinc can prevent ischemia reperfusion injury by activating phosphoinositide-3 kinase (PI3K)/Akt and by targeting the mitochondrial permeability transition pore (mPTP). It is known that ErbB2 expression promotes association and activation of PI3-kinase/Akt, resulting in growth and survival of cardiac myocytes. In this study, we found that zinc-induced ErbB2 protein expression and Akt activation are required for preventing reperfusion injury. Neonatal rat cardiac myocytes subjected to 8 h of hypoxia, followed by 16 h of reoxygenation induced cardiomyocyte apoptosis, as assessed by increased caspase-3 activity, annexin V staining and lowered MTT reduction and ATP levels. However, addition of zinc-pyrithione (ZPT) before onset of reoxygenation effectively lowered the apoptotic indices and restored the ATP levels. ZPT induced a significant increase in ErbB2 protein expression and Akt activation. Pretreatment with Hsp 90 inhibitor, geldanamycin or PI3-kinase inhibitor, wortmannin prevented the increase in ATP levels and abrogated the protective effect of zinc-pyrithione. Taken together, these data suggest that zinc prevents reperfusion injury by modulating the ErbB2 protein expression and Akt activation.