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(Circulation. 2005;111:90-96.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Role of Omi/HtrA2 in Apoptotic Cell Death After Myocardial Ischemia and Reperfusion

Hui-Rong Liu, MD, PhD; Erhe Gao, MD, PhD; Aihua Hu, MD, PhD; Ling Tao, MD; Yan Qu, MD; Patrick Most, PhD; Walter J. Koch, PhD; Theodore A. Christopher, MD; Bernard L. Lopez, MD; Emad S. Alnemri, PhD; Antonis S. Zervos, PhD; Xin L. Ma, MD, PhD

From the Department of Emergency Medicine (H.-R.L., A.H., L.T., Y.Q., T.A.C., B.L.L., X.L.M.), Thomas Jefferson University, Philadelphia, Pa; the Center for Translational Medicine (E.G., P.M., W.J.K.), Thomas Jefferson University, Philadelphia, Pa; the Center for Apoptosis Research (E.S.A.), Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pa; and the Biomolecular Science Center and Department of Molecular Biology and Microbiology (A.S.Z.), University of Central Florida, Orlando, Fla.

Correspondence to Xin L. Ma, MD, PhD, Department of Emergency Medicine, Jefferson Medical College, 1020 Sansom St, Philadelphia, PA 19107-5004 (e-mail Xin.Ma{at}jefferson.edu); or Hui-Rong Liu, MD, PhD, Department of Physiology, Shangxi Medical University, Taiyuan, Shangxi, PR China (e-mail liuhr2000@hotmail.com).

Received August 9, 2004; revision received September 21, 2004; accepted September 30, 2004.

Background— Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent as well as caspase-independent cell death. However, the role of Omi/HtrA2 in the apoptotic cell death that occurs in vivo under pathological conditions remains unknown. The present study was designed to investigate whether Omi/HtrA2 plays an important role in postischemic myocardial apoptosis.

Methods and Results— Male adult mice were subjected to 30 minutes of myocardial ischemia followed by reperfusion and treated with vehicle or ucf-101, a novel and specific Omi/HtrA2 inhibitor, 10 minutes before reperfusion. Myocardial ischemia/reperfusion significantly increased cytosolic Omi/HtrA2 content and markedly increased apoptosis. Treatment with ucf-101 exerted significant cardioprotective effects, as evidenced by less terminal dUTP nick end-labeling staining, a lower incidence of DNA ladder fragmentation, and smaller infarct size. Furthermore, treatment with ucf-101 before reperfusion attenuated X-linked inhibitor of apoptosis protein degradation and inhibited caspase-9 and caspase-3 activities.

Conclusion— Taken together, these results demonstrate for the first time that ischemia/reperfusion results in Omi/HtrA2 translocation from the mitochondria to the cytosol, where it promotes cardiomyocyte apoptosis via a protease activity–dependent, caspase-mediated pathway.

Key Words: apoptosis • myocardial infarction • reperfusion

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