Abstract
Myocardial apoptosis is a significant problem underlying ischemic heart disease. We previously reported significantly elevated expression of cytoplasmic Omi/HtrA2, triggers cardiomyocytes apoptosis. However, whether increased Omi/HtrA2 within mitochondria itself influences myocardial survival in vivo is unknown. We aim to observe the effects of mitochondria-specific, not cytoplasmic, Omi/HtrA2 on myocardial apoptosis and cardiac function. Transgenic mice overexpressing cardiac-specific mitochondrial Omi/HtrA2 were generated and they had increased myocardial apoptosis, decreased systolic and diastolic function, and decreased left ventricular remodeling. Transiently or stably overexpression of mitochondria Omi/HtrA2 in H9C2 cells enhance apoptosis as evidenced by elevated caspase-3, -9 activity and TUNEL staining, which was completely blocked by Ucf-101, a specific Omi/HtrA2 inhibitor. Mechanistic studies revealed mitochondrial Omi/HtrA2 overexpression degraded the mitochondrial anti-apoptotic protein HAX-1, an effect attenuated by Ucf-101. Additionally, transfected cells overexpressing mitochondrial Omi/HtrA2 were more sensitive to hypoxia and reoxygenation (H/R) induced apoptosis. Cyclosporine A (CsA), a mitochondrial permeability transition inhibitor, blocked translocation of Omi/HtrA2 from mitochondrial to cytoplasm, and protected transfected cells incompletely against H/R-induced caspase-3 activation. We report in vitro and in vivo overexpression of mitochondrial Omi/HtrA2 induces cardiac apoptosis and dysfunction. Thus, strategies to directly inhibit Omi/HtrA2 or its cytosolic translocation from mitochondria may protect against heart injury.
Highlights
Omi/HtrA2 is a proapoptotic mitochondrial serine protease that is released into the cytoplasm following apoptotic insult[7]
Myocardial morphometric and functional observations from the present study indicate that cardiac-specific overexpression of Omi/HtrA2 in the mitochondria significantly induced myocardial apoptosis, cardiac remodeling, and cardiac dysfunction that resembles dilated cardiomyopathy
Our and other’s previous studies showed the expression of Omi/HtrA2 is increased in the aging heart, which promotes cardiomyocyte apoptosis via degradation of XIAP and plays a causative role in enhanced post-ischemic injury in the aging heart[10,17]
Summary
Omi/HtrA2 is a proapoptotic mitochondrial serine protease that is released into the cytoplasm following apoptotic insult[7]. It complexes with different inhibitors-of-apoptosis proteins (IAPs), preventing their ability to bind and attenuate caspases[8]. We previously reported that myocardial ischemia/reperfusion (MI/R) resulted in the translocation of Omi/HtrA2 from the mitochondria to the cytoplasm, promoting cardiomyocyte apoptosis[9]. Subsequent studies have confirmed similar results regarding translocation of Omi/HtrA2 in both myocardial and cerebral ischemia/reperfusion models[11,12]. The aims of the present study were (1) to determine the effect of cardiac specific overexpression of intra-mitochondrial Omi/HtrA2 on cardiac structure and function; (2) to ascertain whether intra-mitochondrial Omi/HtrA2 directly promotes cardiomyocyte apoptosis, and to investigate the possible mechanisms
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