Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy

Cardiac hypertrophy is a major cause of morbidity and mortality worldwide. The hypertrophic process is mediated, in part, by small G proteins of the R ho family. We hypothesized that statins, inhibitors of 3-hydroxy-3-methylgl utaryl-CoA reductase, inhibit cardiac hypertrophy by blocking Rho isoprenyl ation. We treated neonatal rat cardiac myocytes with angiotensin II (AngII) with and without simvastatin (Sim) and found that Sim decreased AngII-indu ced protein content, [H-3] leucine uptake, and atrial natriuretic factor (A NF) promoter activity. These effects were associated with decreases in cell size, membrane Rho activity, superoxide anion (O-2.(-)) production, and in tracellular oxidation, and were reversed with L-mevalonate or geranylgerany lpyrophosphate, but not with farnesylpyrophosphate or cholesterol. Treatmen ts with the Rho inhibitor C3 exotoxin and with cell-permeable superoxide di smutase also decreased AngII-induced O-2.(-) production and myocyte hypertr ophy. Overexpression of the dominant-negative Rho mutant N17Rac1 completely inhibited AngII-induced intracellular oxidation and ANF promoter activity, while N19RhoA partially inhibited it, and N17Cdc42 had no effect. Indeed, Sim inhibited cardiac hypertrophy and decreased myocardial Rac1 activity an d O-2.(-) production in rats treated with AngII infusion or subjected to tr ansaortic constriction. These findings suggest that statins prevent the dev elopment of cardiac hypertrophy through an antioxidant mechanism involving inhibition of Rac1.