Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy
Masao Takemoto, … , Masafumi Kitakaze, James K. Liao
Masao Takemoto, … , Masafumi Kitakaze, James K. Liao
Published November 15, 2001
Citation Information: J Clin Invest. 2001;108(10):1429-1437. https://doi.org/10.1172/JCI13350.
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Article

Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy

Abstract

Cardiac hypertrophy is a major cause of morbidity and mortality worldwide. The hypertrophic process is mediated, in part, by small G proteins of the Rho family. We hypothesized that statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, inhibit cardiac hypertrophy by blocking Rho isoprenylation. We treated neonatal rat cardiac myocytes with angiotensin II (AngII) with and without simvastatin (Sim) and found that Sim decreased AngII-induced protein content, [3H] leucine uptake, and atrial natriuretic factor (ANF) promoter activity. These effects were associated with decreases in cell size, membrane Rho activity, superoxide anion (O2·̄) production, and intracellular oxidation, and were reversed with L-mevalonate or geranylgeranylpyrophosphate, but not with farnesylpyrophosphate or cholesterol. Treatments with the Rho inhibitor C3 exotoxin and with cell-permeable superoxide dismutase also decreased AngII-induced O2·̄ production and myocyte hypertrophy. 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 and O2·̄ production in rats treated with AngII infusion or subjected to transaortic constriction. These findings suggest that statins prevent the development of cardiac hypertrophy through an antioxidant mechanism involving inhibition of Rac1.

Authors

Masao Takemoto, Koichi Node, Hironori Nakagami, Yulin Liao, Michael Grimm, Yaeko Takemoto, Masafumi Kitakaze, James K. Liao

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Inhibition of cardiac sarcomere organization, myocyte size, and fetal ge...
Inhibition of cardiac sarcomere organization, myocyte size, and fetal gene expression by statins. (a) Effects of AngII with and without Sim (5 μM) on cardiac myocyte size and sarcomere organization. Double immunofluorescent microscopy was performed using specific antibodies to desmin (upper panel, red color) and α-actinin (lower panel, green color). Experiments were performed three times with similar results. Effect of AngII with and without Sim (5 μM) on steady-state (b) ANF and (c) MLC-2v mRNA expression after 24 hours of treatment. Corresponding ethidium bromide–stained 28S ribosomal RNA was used to standardize loading. The results shown are representative of three separate experiments.