Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts

Objective: Due to reported modulatory effects of statins on nitric oxide synthase (NOS) expression, we tested the hypothesis of protective effects of in vivo chronic treatment with rosuvastatin, a novel 3-hydroxy-3-methyl-glutaryl coenzyme A-reductase inhibitor, on ischemia-reperfusion injury, and investigated mechanisms involved. Methods: After 3 weeks of in vivo treatment with rosuvastatin (0.2-20 mg/kg/day) or placebo, excised hearts from Wistar rats were subjected to 15 min global ischemia and 22-180 min reperfusion. We evaluated creatine-phosphokinase and nitrite levels in the coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcription polymerase chain reaction and Western blotting). Results: Rosuvastatin 0.2 and 2 mg/kg/day significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. At 2 mg/kg/day, rosuvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, and conversely decreased iNOS mRNA and protein, as well as nitrite production after ischemia reperfusion. The addition of the NOS inhibitor N-infinity-nitro-L-arginine methylester (L-NAME, 30 mu mol/L) significantly reduced cardioprotection against ischemia-reperfusion. Conclusions: Chronic treatment with rosuvastatin before ischemia reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by NO-dependent mechanisms. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.