Published online before print July 20, 2006, doi: 10.1161/01.RES.0000237387.05259.a5
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Submitted on February 21, 2005
Revised on June 12, 2006
Accepted on July 11, 2006
Overexpression of HAX-1 Protects Cardiac Myocytes From Apoptosis Through Caspase-9 Inhibition
Yuchi Han ;
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.
* To whom correspondence should be addressed. 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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