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This Article Full Text Full Text (PDF) All Versions of this Article: 291/6/H2743    most recent 00347.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Greer, J. J. M. Articles by Lefer, D. J. Search for Related Content PubMed PubMed Citation Articles by Greer, J. J. M. Articles by Lefer, D. J.

Low-dose simvastatin improves survival and ventricular function via eNOS in congestive heart failure

¹Department of Molecular and Cellular Physiology, ²Division of Cardiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana; ³Division of Cardiology and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; and ⁴Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky

Submitted 31 March 2006 ; accepted in final form 12 July 2006

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase endothelial nitric oxide synthase (eNOS) activity by multiple mechanisms. We previously reported that genetic overexpression of eNOS improves survival and cardiac function in congestive heart failure (CHF). In the present study, we tested the hypothesis that low-dose treatment with an 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor exerts beneficial effects on survival and/or cardiac function in a murine model of CHF. Mice were subjected to permanent ligation of the left coronary artery and randomized to receive either saline vehicle or simvastatin (0.25 mg/kg) 2 h after myocardial infarction and daily (0.25 mg/kg) for 7 days, followed by 21 days of administration every other day for a total duration of 28 days. Myocardial infarct size was not reduced by simvastatin therapy (P = not significant between groups). Simvastatin treatment did significantly (P < 0.05) improve survival (45%) compared with vehicle treatment (25%). In addition, simvastatin treatment significantly improved (P < 0.01) left ventricular function and significantly (P < 0.01) abrogated cardiac hypertrophy and pulmonary edema compared with vehicle treatment. The protective effects of simvastatin were abrogated by delayed initiation of treatment or genetic ablation of eNOS. In conclusion, low-dose simvastatin therapy significantly improves survival and cardiac function and reduces both cardiac hypertrophy and pulmonary edema via an eNOS-dependent mechanism in a murine model of CHF.

nitric oxide; 3-hydroxy-3-methylglutaryl coenzyme A; myocardial infarction; ventricular remodeling; echocardiography

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