Role of extracellular signal-regulated kinase in cardioprotective and anti-apoptotic effects of nitric oxide after myocardial ischemia and reperfusion

Abstract

Objective To determine whether extracellular signal-regulated kinase (ERK) participates in the whole organ or whole animal level in the cardioprotective and anti-apoptotic effects of nitric oxide (NO) during myocardial ischemia/reperfusion (MI/R) injury and the mechanism of ERK and NO in anti-apoptotic effect. Methods Isolated perfused mouse hearts were subjected to 20 min of global ischemi-a and 120 min of reperfusion. During reperfusion period, the hearts were treated with either vehicle or NO donor (SNAP, 10μmol/L). To determine the role of ERK in the anti-apoptotic and cardioprotective effects of NO, some mouse hearts were pre-treated (10 min before ischemia) with U0126, a selective MEK1/2 inhibitor (1μmol/L). Results The group treated with SNAP showed marked myocardial protection effect. Their apoptosis is obviously inhibited (TUNEL and Caspase-3 activity,P <0.01). Their cardiac functional recovery was better (P<0.01). Besides, as compared with vehicle group, treatment with SNAP resulted in a 2. 5-fold increase in ERK activation. Pre-treatment with U0126 slightly increased post-ischemic myocardial apoptosis but showed httle effect on cardiac functional recovery. However, U0126 completely blocked ERK activation induced by SNAP and markedly, although not completely, blocked the cardiac protective effect of SNAP. Conclusion The anti-apoptotic and myocardial protection effect of NO is at least in part, mediated through activation of ERK in ischemic/reperfused heart. Key words: Nitric oxide; ERK; Myocardial ischemia; Reperfusion injure; Apoptosis