Published Online
on September 23, 2002

A more recent version of this article appeared on October 15, 2002

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Submitted on April 4, 2002
Revised on July 23, 2002
Accepted on July 23, 2002

Hydroxymethylglutaryl Coenzyme A Reductase Inhibitor Simvastatin Prevents Cardiac Hypertrophy Induced by Pressure Overload and Inhibits p21ras Activation

Ciro Indolfi MD^*, Emilio Di Lorenzo MD, Cinzia Perrino MD, Angela Maria Stingone MD, Antonio Curcio MD, Daniele Torella MD, Antonello Cittadini MD, Luca Cardone PhD, Carmela Coppola MD, Luigi Cavuto MD, Oreste Arcucci MD, Luigi Sacca MD, Enrico Vittorio Avvedimento MD, and Massimo Chiariello MD

From the Division of Cardiology (C.I., A. Curcio), Magna Graecia University, Catanzaro; Division of Cardiology (E.D.L., C.P., A.M.S., D.T., C.C., L. Cavuto, O.A., M.C.), Department of Medicine (A. Cittadini., L.S.), and Department of Biology and Molecular and Cellular Pathology (L. Cardone, E.V.A.), University Federico II, Naples, Italy.

^* To whom correspondence should be addressed. E-mail: indolfi{at}unicz.it.

Background—Patients with cardiac hypertrophy are at increased cardiovascular risk. It has been hypothesized that hydroxymethylglutaryl coenzyme A reductase inhibitors may exert beneficial effects other than their cholesterol-lowering actions. The aims of the study were to assess the in vivo effects of simvastatin (SIM) on cardiac hypertrophy and on Ras signaling in rats with ascending aorta banding.

Methods and Results—Wistar rats were randomized to receive either treatment with SIM or placebo, and then short-term (group I) and long-term (group II) left ventricular pressure overload was performed by placing a tantalum clip on ascending aorta. At the end of treatment period, left and right ventricular weight, body weight, and tibial length were measured and echocardiographic evaluations were performed. Ras signaling was investigated by analyzing Ras membrane localization and activation, ERK2 phosphorylation, and p27^kip1 and cdk4 levels. In SIM-treated rats, a significant reduction of left ventricular weight/body weight, echocardiographic left ventricular mass, and left ventricular end-diastolic diameter and end-diastolic pressure was found. In rats with pressure overload, SIM treatment significantly reduced Ras membrane targeting, Ras in vivo activation, ERK2 phosphorylation, and the ratio cdk4/p27^kip1.

Conclusions—HMG CoA inhibitor SIM inhibits in vivo Ras signaling and prevents left ventricular hypertrophy development in aortic-banded animals.

Key words: hypertrophy • signal transduction • statins • myocardium • pressure

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