Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia-reperfusion injury ネクロプトーシス、アポトーシス阻害の組み合わせは心筋虚血再灌流障害に対する心保護効果を増強する

Necroptosis has been proposed as a mode of cell death that is a caspase-independent programmed necrosis. We investigated whether necroptosis is involved in myocardial ischemia-reperfusion injury in isolated guinea pig hearts and, if so, whether simultaneous inhibition of necroptosis and apoptosis confers enhanced cardioprotection.

Isolated perfused guinea pig hearts were subjected to 30min ischemia and 4h reperfusion (control=CTL, n=8). Necrostatin-1 (necroptosis inhibitor, 10μM), Z-VAD (apoptosis inhibitor, 0.1μM) and both inhibitors were administered starting 5min before ischemia and during the initial 30min of reperfusion (Nec, Z-VAD, Nec+Z-VAD; n=8 each). Contractile recovery was monitored by left ventricular developed (LVDP) and end-diastolic (LVEDP) pressure. Infarct size was determined by triphenyltetrazolium chloride staining. Tissue samples were obtained after 4h reperfusion to determine expression of receptor-interacting protein 1 (RIP1) and activated caspase 3 by Western blot analysis.

After reperfusion, Nec+Z-VAD had higher LVDP and lower LVEDP compared with CTL. Infarct size was reduced in Nec and Z-VAD compared with CTL. Combination of necroptosis and apoptosis inhibition further reduced infarct size. Expression of activated caspase 3 was not increased in Z-VAD and Nec+Z-VAD compared with Nec and CTL. Expression of RIP1 was preserved in Z-VAD and Nec+Z-VAD compared with CTL, suggesting RIP1-mediated necrosis is involved in myocardial ischemia-reperfusion injury.

Necroptosis is involved in myocardial ischemia-reperfusion injury, and simultaneous inhibition of necroptosis and apoptosis enhances the cardioprotective effect. These findings may provide a novel, additive strategy for cardioprotection in acute myocardial infarction.

2013

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