Cardioprotective effects of PTD-PLC1 protein transduction in ischemic/reperfusion injury and its mechanisms
황기철, 장우철, 임소연, 심지영, 서혜선, 이상규, 장양수, 정남식
서울시 서대문구 신촌동 134번지, 연세대학교 의과대학 심혈관 연구소 심장내과
Background: Myocardial oxidative stress and Ca2+ overload induced by ischemia-reperfusion may be involved in the development and progression of myocardial dysfunction in heart failure. Previously we have shown that PLC-δ1, but not PLC-β1 and PLC-γ1, was selectively degraded in ischemic heart and hypoxic neonatal cardiomyocytes, leading to intracellular Ca2+ overload. The present study was designed to determine whether PTD-PLC1 protein may have cardioprotective effects against myocardial ischemia/reperfusion (I/R) injury and, if so, to determine the mechanisms involved. Methods and Results: In vitro, transduction of PTD-PLC1 inhibited death and intracellular Ca2+ overload of hypoxic cardiomyocytes in a dose-dependent manner. PTD-PLC1 also prevented mitochondrial permeability transition pore (mPTP) opening in H2O2-stimulated cardiomyocytes. In vivo, rat hearts (n=8 per group) were subjected to a 60-min occlusion of LAD by 2 weeks of reperfusion. In contrast to the I/R control group, intravenous injection of 30 nM of PTD-PLC1 resulted in a significant reduction in the infarct size and an improvement in systolic and diastolic cardiac function by transthoracic echocardiography. TUNEL-positive cells in the ischemic myocardium were also significantly reduced in the I/R + PTD-PLC1, consistent with little DNA laddering. Furthermore, greater Bcl-2 and attenuated Bax expression was found in the PTD-PLC1 treated rats. Conclusion: Our findings show that transduction of PTD-PLC1 reduce ischemia-reperfusion injury by preventing apoptosis through inhibition of Ca2+ overload and mPTP opening.
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