Published online before print April 22, 2004, doi: 10.1161/01.RES.0000129179.66631.00
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© 2004 American Heart Association, Inc.
Cellular Biology |
Small Heat-Shock Protein Hsp20 Phosphorylation Inhibits ß-Agonist-Induced Cardiac Apoptosis
From the Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Ohio.
Correspondence to Dr Evangelia G. Kranias, Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575. E-mail Litsa.Kranias{at}uc.edu
Activation of the sympathetic nervous system is a common compensatory feature in heart failure, but sustained ß-adrenergic activation induces cardiomyocyte death, leading to cardiac remodeling and dysfunction. In mouse cardiomyocytes, we recently reported that prolonged exposure to ß-agonists is associated with transient increases in expression and phosphorylation of a small heat-shock protein, Hsp20. To determine the functional significance of Hsp20, we overexpressed this protein and its constitutively phosphorylated (S16D) or nonphosphorylated (S16A) mutant in adult rat cardiomyocytes. Hsp20 protected cardiomyocytes from apoptosis triggered by activation of the cAMP-PKA pathway, as indicated by decreases in the number of pyknotic nuclei, terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling, and DNA laddering, which were associated with inhibition of caspase-3 activity. These protective effects were further increased by the constitutively phosphorylated Hsp20 mutant (S16D), which conferred full protection from apoptosis. In contrast, the nonphosphorylatable mutant (S16A) exhibited no antiapoptotic properties. Immunostaining studies and immunoprecipitations with Hsp20 or actin antibodies demonstrated that Hsp20 translocated to cytoskeleton and associated with actin on isoproterenol stimulation. These findings suggest that Hsp20 and its phosphorylation at Ser16 may provide cardioprotection against ß-agonist-induced apoptosis. Thus, Hsp20 may represent a novel therapeutic target in the treatment of heart failure.
Key Words: apoptosis • ß-agonist • small heat-shock protein • cardiomyocyte • cytoskeleton
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