Published Online
on July 19, 2004

A more recent version of this article appeared on July 27, 2004

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Submitted on July 23, 2003
Revised on March 17, 2004
Accepted on March 22, 2004

Statins Inhibit -Adrenergic Receptor-Stimulated Apoptosis in Adult Rat Ventricular Myocytes via a Rac1-Dependent Mechanism

Masahiro Ito MD, Takeshi Adachi MD, David R. Pimentel MD, Yasuo Ido MD, and Wilson S. Colucci MD^*

From the Cardiovascular (M.I., D.R.P., W.S.C.) and Endocrinology (Y.I.) Divisions, Department of Medicine, Boston University Medical Center, and Myocardial Biology (M.I., D.R.P., W.S.C.), Vascular Biology (T.A.), and Diabetes and Metabolism Units (Y.I.), Boston University School of Medicine, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: Wilson.Colucci{at}bmc.org.

Background--3-Hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) inhibit myocyte hypertrophy in vitro and ameliorate the progression of cardiac remodeling in vivo, possibly because of inhibition of the small GTPase Rac1. The role of Rac1 in mediating myocyte apoptosis is not known. -Adrenergic receptor (AR)-stimulated myocyte apoptosis is mediated via activation of c-Jun NH₂-terminal kinase (JNK), leading to activation of the mitochondrial death pathway. We hypothesized that AR-stimulated apoptosis in adult rat ventricular myocyte (ARVMs) is mediated by Rac1 and inhibited by statins.

Methods and Results--AR stimulation increased apoptosis, as assessed by transferase-mediated nick-end labeling, from 5±1% to 24±2%. AR stimulation also increased Rac1 activity. Adenoviral overexpression of a dominant-negative mutant of Rac1 inhibited AR-stimulated apoptosis, JNK activation, cytochrome C release, and caspase-3 activation. Cerivastatin likewise inhibited the AR-stimulated activation of Rac1, decreased AR-stimulated apoptosis to 11±2%, and inhibited JNK activation, cytochrome C release, and caspase-3 activation.

Conclusions--AR stimulation causes Rac1 activation, which is required for myocyte apoptosis and leads to activation of JNK and the mitochondrial death pathway. Cerivastatin inhibits AR-stimulated activation of Rac1 and thereby inhibits JNK-dependent activation of the mitochondrial death pathway and apoptosis. The beneficial effects of statins on the myocardium may be mediated in part via inhibition of Rac1-dependent myocyte apoptosis.

Key words: apoptosis • hydroxymethylglutaryl-CoA reductase inhibitors • myocytes • rac1 GTP-binding protein • receptors, adrenergic, beta

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