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Submitted on October 4, 2006
Accepted on February 1, 2007
University of Missouri School of Medicine, Diabetes and Cardiovascular Lab, and Harry S Truman VA Medical Center, Wake Forest University School of Medicine, SUNY Stony Brook School of Medicine at Winthrop-University Hospital, and The New York Harbor VA Health Care System, Brooklyn Campus, NY, University of Arizona, and Arizona VA Medical Center, Tucson, AZ
* To whom correspondence should be addressed. E-mail: sowersj{at}deptofmed.arizona.edu.
Angiotensin-II (Ang-II)-stimulated increases in 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 anti-oxidant 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 6-7-week old Ren2 rats and age-matched Sprague-Dawley (SD) rats with rosuvastatin (10mg/kg/day) or vehicle for three weeks. 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 (MDA), NADPH-oxidase subunits (gp91phox, p40phox, and p22phox) and Rac1 were analyzed by immunochemistry. Systolic blood pressure (SBP) was significantly higher in Ren2 compared to SD rats (p<0.05); rosuvastatin had no significant effect on SBP 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 gp91phox, p40phox, p22phox, and Rac1 expression. These changes were accompanied by a parallel reduction in myocardial lipid peroxidation (nitrotyrosine and MDA 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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