Abstract 15910: Increased Expression of Omi/HtrA2: A Novel Mechanism for Enhanced Myocardial Ischemia/Reperfusion Injury in the Aging Heart
Introduction: Survival after acute myocardial infarction is decreased in elderly patients. We have recently demonstrated that Omi/HtrA2, a potent pro-apoptotic protein, was increased in the aged rats’ hearts. However, the implicative role of Omi/HtrA2 in aging myocardial ischemia/reperfusion (MI/R) remains unknown.
Objective: Using an in vivo MI/R rat model, we attempted to determine whether Omi/HtrA2 was involved in aging increased susceptibility to MI/R and investigated the potential mechanisms.
Method and Results: Male aged or adult rats were subjected to 30 min of myocardial ischemia followed by reperfusion and treated with vehicle or Ucf-101, a specific Omi/HtrA2 inhibitor, 10 min before reperfusion. MI/R-induced cardiac injury was enhanced in aging rats (20 months) as evidenced by aggravated cardiac dysfunction (LVSP: 50.1±19.7mmHg vs. 89.7±8.40mmHg; +dp/dtmax,1.94±0.37mmHg/ms vs. 2.74±0.27 mmHg/ms; p<0.05), increased apoptosis (TUNEL: 19.0±2.1% vs.14.6±1.7%; Caspase3 Activity Ratio: 1.28±0.33 vs.1.00±0.03; p<0.05), and enlarged myocardial infarct size (54.4±2.14% vs. 40.7±2.32%, p<0.01). The translocation of Omi/HtrA2 from mitochondria to cytosol was increased in aging heart that had undergone ischemia (30 minutes) and reperfusion (3 hours). The cytosolic Omi/HtrA2 in aging myocardium was higher than that in adult heart after MI/R. XIAP, a cytosolic protein that blocks apoptosis at a post-mitochondrial level, was decreased in aging heart after MI/R, and lower than that in adult heart after MI/R. Treatment with Ucf-101 attenuated XIAP degradation and exerted cardioprotective effects, which were proved by ameliorated cardiac function (LVSP: 75.2±6.28mmHg vs. 53.2±12.4mmHg; +dp/dtmax, 3.46±0.44mmHg/ms vs. 2.13±0.25mmHg/ms, p<0.05) and decreased Caspase-3 Activity Ratio (1.00±0.11 vs.1.43±0.15, p<0.01). Furthermore, LC3-II, one of the markers of autophagy, was significant decreased after the treatment with Ucf-101 in aging heart, indicated Omi/HtrA2 might be a positive regulator in aging myocardial autophagy.
Conclusion: Our results demonstrated that translocation of Omi/HtrA2 from the mitochondria to the cytosol enhanced MI/R injury in aging heart via promoting myocardial apoptosis and probably autophagy.
- © 2011 by American Heart Association, Inc.