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Rosuvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Decreases Cardiac Oxidative Stress and Remodeling in Ren2 Transgenic Rats

University of Missouri School of Medicine (J.H., A.W.-C., M.R.H., J.T., J.R.S.), Diabetes and Cardiovascular Laboratory (J.H., A.W.-C., M.Q., M.R.H., J.T., J.R.S.), and Harry S. Truman Veterans Affairs Medical Center (J.H., A.W.-C., J.T., J.R.S.), Columbia, Missouri 65212; Wake Forest University School of Medicine (C.F.), Winston-Salem, North Carolina 27157; State University of New York, Stony Brook, School of Medicine at Winthrop-University Hospital (A.T.), Stony Brook, New York 11794; The New York Harbor Veterans Affairs Healthcare System (R.M.), Brooklyn Campus, Brooklyn, New York 11209; and University of Arizona and Arizona Veterans Affairs Medical Center (S.A.C., C.S.), Tucson, Arizona 85724-5218

Address all correspondence and requests for reprints to: James R. Sowers, M.D., F.A.C.E., F.A.C.P., F.A.H.A., Professor of Medicine and Physiology, Department of Internal Medicine, Division of Endocrinology, D109 HSC Diabetes Center, Columbia, Missouri 65212. E-mail: sowersj{at}deptofmed.arizona.edu.

Angiotensin-II (Ang-II)-stimulated increases in nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity and oxidative stress are known to play a key role in cardiac remodeling. Inhibition of isoprenylation and activation of small G proteins, such as Rac1, a component of NADPH oxidase, may mediate the antioxidant actions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). In this study, we investigated the effects of rosuvastatin on cardiac oxidative stress and remodeling in transgenic rats (Ren2) overexpressing the mouse renin gene with elevated cardiac levels of Ang-II. We treated 6- to 7-wk-old Ren2 rats and age-matched Sprague-Dawley (SD) rats with rosuvastatin (10 mg/kg·d) or vehicle for 3 wk. At the end of the treatment period, left ventricular mass, wall thickness, ejection fraction (by echocardiography), and cardiac remodeling (by light microscopy and immunohistochemistry) were assessed. In addition, myocardial content of nitrotyrosine, malondialdehyde, NADPH-oxidase subunits (gp91^phox, p40^phox, and p22^phox), and Rac1 were analyzed by immunochemistry. Systolic blood pressure was significantly higher in Ren2 rats, compared with SD rats (P < 0.05); rosuvastatin had no significant effect on systolic blood pressure in either group. In Ren2, but not SD rats, rosuvastatin significantly improved the ventricular ejection fraction, cardiac hypertrophy, and perivascular fibrosis (P < 0.05). In addition, rosuvastatin administration significantly decreased the accentuated myocardial gp91^phox, p40^phox, p22^phox, and Rac1 expression. These changes were accompanied by a parallel reduction in myocardial lipid peroxidation (nitrotyrosine and malondialdehyde content) (P < 0.05). These results suggest that in vivo statin treatment through its direct actions on the heart reduces oxidative stress and remodeling including ventricular mass regression in the Ang-II-dependent Ren2 model.

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