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Circulation. 2004 Jul 27;110(4):412-8. Epub 2004 Jul 19.

Statins inhibit beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes via a Rac1-dependent mechanism.

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  • 1Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA.



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. beta-Adrenergic receptor (betaAR)-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 betaAR-stimulated apoptosis in adult rat ventricular myocyte (ARVMs) is mediated by Rac1 and inhibited by statins.


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


betaAR stimulation causes Rac1 activation, which is required for myocyte apoptosis and leads to activation of JNK and the mitochondrial death pathway. Cerivastatin inhibits betaAR-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.

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