Title

Role of Omi/HtrA2 in apoptotic cell death after myocardial ischemia and reperfusion

Authors

Authors

H. R. Liu; E. Gao; A. H. Hu; L. Tao; Y. Qu; P. Most; W. J. Koch; T. A. Christopher; B. L. Lopez; E. S. Alnemri; A. S. Zervos;X. L. Ma

Comments

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Abbreviated Journal Title

Circulation

Keywords

apoptosis; myocardial infarction; reperfusion; SERINE-PROTEASE OMI/HTRA2; CASPASE ACTIVITY; INHIBITOR; PROTEINS; MITOCHONDRIA; XIAP; SMAC/DIABLO; INTERACTS; HTRA2; MICE; Cardiac & Cardiovascular Systems; Peripheral Vascular Disease

Abstract

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.

Journal Title

Circulation

Volume

111

Issue/Number

1

Publication Date

1-1-2005

Document Type

Article

Language

English

First Page

90

Last Page

96

WOS Identifier

WOS:000226065300015

ISSN

0009-7322

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