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

Abstract

-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 ϭ not significant between groups). Simvastatin treatment did significantly (P Ͻ 0.05) improve survival (45%) compared with vehicle treatment (25%). In addition, simvastatin treatment significantly improved (P Ͻ 0.01) left ventricular function and significantly (P Ͻ 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.

O-linked β- N -acetylglucosamine transferase is indispensable in the failing heart

“…Adult (3-4 mo old) mice were subjected to in vivo coronary ligation to induce heart failure, as described previously (20)(21)(22). Using sterile technique, mice were subjected to a thoracotomy and the left coronary artery visualized and permanently occluded with the aid of a dissecting microscope.…”

“…Transthoracic echocardiography of the left ventricle using a 15-MHz linear array transducer (15L8) interfaced with a Sequoia C512 system (Acuson) was performed as previously described (20)(21)(22). At the indicated times, mice were anesthetized with 2% isoflurane, maintained under anesthesia with 1.25% isoflurane, and examined.…”

Spectrum of Pleiotropic Effects of Statins in Heart Failure

“…[19] Statins enhance endothelial nitric oxide synthase via stabilization of eNOS mRNA through inhibition of Rho, and phosphorylation of eNOS protein by activation of the phosphatidylinositol 3-kinase/Akt pathway. [20] Simvastatin has been shown to stabilize eNOS mRNA, whereas simvastatin and lovastatin have been shown to upregulate eNOS expression. [21,22] In an ischemic model of heart failure induced by ligation of the left anterior descending artery low dose simvastatin was shown to decrease the severity of heart failure.…”

“…The salutary effects of simvastatin were not evident in eNOS deficient mice (eNOS -/-), suggesting that eNOS is required for the beneficial effects of simvastatin in this model. [20] Endothelin-1 is a 21 amino acid peptide that acts on ET A receptors on endothelial cells to cause vasoconstriction. Atorvastatin and simvastatin inhibit pre-proET-1 mRNA expression and ET-1 synthesis.…”

Short-term therapy with simvastatin reduces inflammatory mediators and heart inflammation during the acute phase of experimental Chagas disease

“…More recently, by blocking the conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to mevalonate, HMG CoA reductase inhibitors (statins) have emerged as potent inhibitors of cholesterol and isoprenoid biosynthesis (Liao 2002). Furthermore, the pleiotropic effects of statins have been associated with the inhibition of inflammatory cytokine synthesis, a reduction in ventricular remodelling and an improvement in endothelial cell function through the increased production of endothelial nitric oxide and a decrease in the release of endothelin-1 and other inflammatory mediators (Elrod & Lefer 2005, Greer et al 2006, Devaraj et al 2007. Additionally, some studies have also suggested that the specific statin simvastatin may affect immune-mediated inflammation because of the documented ability of this statin to reduce the adhesion of inflammatory cells to the endothelium, inhibit leukocyte adhesion by direct interactions with the leukocyte-function antigen-1 and modulate the expression of the integrin dimer CD11b on monocytes.…”