Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, decreases cardiac oxidative stress and remodeling in Ren2 transgenic rats

Javad Habibi, Adam Whaley-Connell, Mahnaz A. Qazi, Melvin R. Hayden, Shawna A. Cooper, Anthony Tramontano, John Thyfault, Craig Stump, Carlos Ferrario, Ranganath Muniyappa, James R. Sowers

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

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 (gp91phox, p40phox, and p22phox), 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, p40phox, p22phox, 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.

Original languageEnglish (US)
Pages (from-to)2181-2188
Number of pages8
JournalEndocrinology
Volume148
Issue number5
DOIs
StatePublished - May 1 2007

ASJC Scopus subject areas

  • Endocrinology

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    Habibi, J., Whaley-Connell, A., Qazi, M. A., Hayden, M. R., Cooper, S. A., Tramontano, A., Thyfault, J., Stump, C., Ferrario, C., Muniyappa, R., & Sowers, J. R. (2007). Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, decreases cardiac oxidative stress and remodeling in Ren2 transgenic rats. Endocrinology, 148(5), 2181-2188. https://doi.org/10.1210/en.2006-1355