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

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. β-Adrenergic receptor (βAR)-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 βAR-stimulated apoptosis in adult rat ventricular myocyte (ARVMs) is mediated by Rac1 and inhibited by statins. Methods and Results— βAR stimulation increased apoptosis, as assessed by transferase-mediated nick-end labeling, from 5±1% to 24±2%. βAR stimulation also increased Rac1 activity. Adenoviral overexpression of a dominant-negative mutant of Rac1 inhibited βAR-stimulated apoptosis, JNK activation, cytochrome C release, and caspase-3 activation. Cerivastatin likewise inhibited the βAR-stimulated activation of Rac1, decrea...