Survivin: A novel player in insulin cardioprotection against myocardial ischemia/reperfusion injury

Insulin inhibits ischemia/reperfusion-induced myocardial apoptosis through the activation of a survival signaling cascade including the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. However, the downstream mechanism of PI3K remains elusive. This study is aimed at investigating whether survivin (SW) plays a role in the insulin-induced anti-apoptotic effect in the ischemic/reperfused (I/R) hearts, and if so, further determining the signaling mechanism involved. Isolated adult rat hearts were subjected to 30 min regional ischemia followed by reperfusion with or without insulin (10(-7) mol/L) at the onset of reperfusion. Reperfusion with insulin inhibited myocardial apoptosis and reduced infarct size, along with significantly up-regulated myocardial SW expression (5.9 +/- 0.3 Group MI/R + Ins vs. 2.1 +/- 0.1 Group MI/R, p<0.05) and increased phosphorylations of mTOR and p70S6K compared with I/R group, which was blocked by pretreatment of PI3K inhibitor LY294002. Rapamycin, a specific mTOR inhibitor, did not alter insulin-induced Akt phosphorylation but significantly inhibited SW expression (from 6.1 +/- 0.3 to 3.0 +/- 0.15. p<0.05). Moreover, rapamycin blunted insulin-induced anti-apoptosis in the I/R hearts (8.1 +/- 0.4% vs. 16.5 +/- 1.8%, p<0.05). To further ascertain the role of SW in insulin-induced cardioprotection, cardiomyocytes were transfected with adenovirus encoding SW (gain-of-function) or siRNA targeting SW (loss-of-function). Overexpression of SW decreased I/R-induced cardiomyocyte apoptosis in vitro, while siRNA targeting SVV significantly blunted the anti-apoptotic effect of insulin. Taken together, these results suggest a novel role of PI3K/Akt/mTOR/SVV signaling in the cardioprotective effect of insulin. (C) 2010 Elsevier Ltd. All rights reserved.