Hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibits p21ras activation.
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.


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.
Indolfi
Ciro
C
Division of Cardiology, Magna Graecia University, Catanzaro, Italy. indolfi@unicz.it
Di Lorenzo
Emilio
E
Perrino
Cinzia
C
Stingone
Angela Maria
AM
Curcio
Antonio
A
Torella
Daniele
D
Cittadini
Antonello
A
Cardone
Luca
L
Coppola
Carmela
C
Cavuto
Luigi
L
Arcucci
Oreste
O
Sacca
Luigi
L
Avvedimento
Enrico Vittorio
EV
Chiariello
Massimo
M
D000818:Animals; D004452:Echocardiography; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D017725:Ventricular Pressure
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)