Published Online
on December 20, 2004

A more recent version of this article appeared on January 4, 2005

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Submitted on August 9, 2004
Revised on September 21, 2004
Accepted on September 30, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: Xin.Ma{at}jefferson.edu.

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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