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(Circulation Research. 2006;99:415.)
© 2006 American Heart Association, Inc.

Cellular Biology

Overexpression of HAX-1 Protects Cardiac Myocytes From Apoptosis Through Caspase-9 Inhibition

Yuchi Han, Yee-Shiuan Chen, Zhilin Liu, Natalya Bodyak, Debra Rigor, Egbert Bisping, William T. Pu, Peter M. Kang

From Cardiovascular Division (Y.H., Y.-S.C., Z.L., N.B., D.R., P.M.K.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass; Department of Cardiology (E.B., W.T.P.), Children’s Hospital Boston, Boston, Mass.

Correspondence to Peter M. Kang, MD, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, SL-423C, Boston, MA 02215. E-mail pkang{at}bidmc.harvard.edu

Caspase-9 is a critical regulator of mitochondria-mediated apoptosis. We found that adult cardiac myocytes, but not nonmyocytes, have high caspase-9 expression, and exhibit relative resistance to caspase-9–induced cell death. Thus, we hypothesized that cardiac myocytes possess factors that resist apoptosis. Through a yeast two-hybrid screening of adult human heart cDNA library, we identified HS-1 associated protein-1 (HAX-1), a 35-kD BH-domain containing protein localized to the mitochondria as one of the molecules that interacts with caspase-9. Recombinant HAX-1 protein inhibited caspase-9 processing in a dose-dependent manner in a cell-free caspase activation assay. Overexpression of HAX-1 in adult cardiac myocytes conferred 30% protection from apoptosis as compared with the control. Suppression of HAX-1 expression using siRNA-HAX-1 resulted in significant cell death in adult cardiac myocytes, suggesting the importance of HAX-1 in cardiac myocyte resistance to apoptotic stimulation. On apoptotic stimulation, some caspase-9 translocated to the mitochondria and co-localized with HAX-1, confirming the spatial proximity of caspase-9 and HAX-1. In summary, HAX-1 is a newly identified anti-apoptotic factor and its mechanism of action is through caspase-9 inhibition.

Key Words: apoptosis • cardiac myocytes • caspase • HAX-1 • mitochondria

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HAX-1 Represses Postmitochondrial Caspase-9 Activation and Cell Death During Hypoxia–Reoxygenation

James Shaw and Lorrie A. Kirshenbaum
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