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Survival after acute myocardial infarction is decreased in elderly patients.The enhanced rates of apoptosis in the aging heart exacerbated myocardial ischemia/reperfusion (MI/R) injury.We have recently demonstrated that the X-linked inhibitor of apoptosis protein (XIAP), the most potent endogenous inhibitor of apoptosis, was decreased in aging rats hearts.XIAP was balanced by two mitochondria proteins, Omi/HtrA2 and Smac/DIABLO.However, the implicative role of XIAP, Omi/HtrA2 and Smac/DIABLO to aging related MI/R injury has not been previously investigated.In our study, male aging rats (20-24 months) or young adult rats (4-6 months) were subjected to 30 min of myocardial ischemia followed by reperfusion.Ml/R-induced cardiac injury was enhanced in aging rats, as evidenced by aggravated cardiac dysfunction, enlarged infarct size and increased myocardial apoptosis (TUNEL and caspase-3 activity).Then, the XIAP, Omi/HtrA2 and Smac/DIABLO protein and mRNA expression was detected.XIAP protein and mRNA expression was decreased in both aging hearts and aging hearts subjected to MI/R.Meanwhile, myocardial XIAP protein expression was correlated to cardiac function after MI/R.However, Omi/HtrA2, but not Smac/DIABLO, expression was increased in aging hearts.Moreover, the translocation of Omi/HtrA2 from mitochondria to cytosol was increased in both aging hearts and aging hearts subjected to MI/R.Treatment with Ucf-101 (a novel and specific Omi/HtrA2 inhibitor) attenuated XIAP degradation and caspase-3 activity and exerted cardioprotective effects.Taken together, these results demonstrated that increased expression and leakage of Omi/HtrA2 enhanced MI/R injury in aging hearts via degrading XIAP and promoting myocardial apoptosis.