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

Abstract

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.

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…Myocyte ErbB2 levels have been shown to decline with metabolic stress (glycolytic or mitochondrial inhibition) associated with ATP depletion (Peng et al, 2005) and hypoxia (Viswanath et al, 2011). Such findings support negative impacts of ischaemic/hypoxic stress on ErbB2 expression and thereby EGFR functionality.…”

Role of Vitamin C in Cardioprotection of Ischemia/Reperfusion Injury by Activation of Mitochondrial K_ATP Channel

“…Cardiac ventricular myocytes were prepared from 1 to 3 d-old neonatal SD rats as previously described. 7,14) OGD/R OGD/R was performed on neonatal rat ventricular myocytes using previously described methods 15,16) with modifications. The cell medium was replaced with glucose-free Dulbecco's modified Eagle's medium (DMEM), which was pre-conducted with a mixture of 5% CO 2 and 95% N 2 for 20 min to remove O 2 .…”

Pre-treatment of a single high-dose of atorvastatin provided cardioprotection in different ischaemia/reperfusion models via activating mitochondrial KATP channel

“…OGD/R was performed on neonatal rat ventricular myocytes using the previously described methods (Viswanath et al, 2011;Wu et al, 2011) with modifications. Cell cultures were subjected to 10 h OGD followed by 3 h recovery.…”