Abstract 1329: Downregulation of XIAP Expression as a cause of Enhanced Myocardial Apoptosis in Aging Hearts
It is well known that myocardial apoptosis is significantly increased in older individuals. Several recent studies have demonstrated that X-linked inhibitor of apoptosis protein (XIAP) is an important anti-apoptotic molecule, which plays a crucial role in the regulation of apoptosis by binding and inhibiting caspases. The present study was designed to determine whether XIAP expression is altered in aging heart, thus contributing to increased susceptibility to apoptosis. Compared with young animals (6 – 8 month), the cardiac function indices markedly declined in aging rats (22–24 month) as evidenced by decreased Cardiac Index (CI, 39.23±1.62 s−1 vs. 46.82±3.176s−1, P<0.01), increased both Left Ventricular Diastolic Pressure (LVDP 0.16±0.17kPa vs. −1.16±0.35kPa, P<0.01) and Left Ventricular End-Diastolic Pressure (LVEDP 1.25±0.35kPa vs. −0.70±0.43kPa, P<0.01). Myocardial apoptosis was significantly higher in the aged heart when compare to the young hearts (TUNEL: 2.86%±0.43% vs. 0.86%±0.29%, caspase-3 activity ratio: 2.21±0.327 vs. 1.00±0.028, P<0.01). XIAP real time-PCR analysis and immunoblot analysis revealed that the abundance of XIAP mRNA and protein in the hearts from aging rats was remarkably lower than that of the young hearts (P<0.05, Figure1). Surprisingly, the expression of an XIAP inhibitor Smac/DIABLO was not significantly changed, indicating that reduced XIAP expression in the aging heart can not be attributed to Smac/DIABLO expression. Interestingly, Omi/HtrA2, a novel mitochondrial-derived pro-apoptotic molecule that blocks the activity of XIAP, was significantly increased as evidenced by increased expression of both mRNA and protein levels in the old group when compared with the young group (P<0.05). Taken together, our results demonstrated that there is decreased expression of XIAP and increased Omi/HtrA2 expression in the aging hearts, while Smac/DIABLO expression is not significantly different between the young and old groups. Interventions that restore XIAP expression or its activity in the aging heart may be a novel therapy to attenuate myocardial apoptosis in the elderly patients.