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Circulation. 2005 Jan 4;111(1):90-6. Epub 2004 Dec 20.

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

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1
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pa, USA.

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.

CONCLUSIONS:

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.

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