Low-dose simvastatin improves survival and ventricular function via eNOS in congestive heart failure.
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.
Greer
James J M
JJ
Department of Molecular and Cellular Physiology, Louisiana State University, Shreveport, USA.
Kakkar
Aman K
AK
Elrod
John W
JW
Watson
Lewis J
LJ
Jones
Steven P
SP
Lefer
David J
DJ
D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000494:pharmacology*; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000201:enzymology; D008055:Lipids / Q000097:blood; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy / Q000201:enzymology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D011654:Pulmonary Edema / Q000188:drug therapy / Q000201:enzymology; D012720:Severity of Illness Index; D019821:Simvastatin / Q000097:blood / Q000494:pharmacology*; D015996:Survival Rate; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III