HMG-CoA reductase inhibition protects the diabetic myocardium from ischemia-reperfusion injury

HMG-CoA reductase inhibitors (statins) exert beneficial effects independently of reducing blood cholesterol levels. We tested the hypothesis that statin therapy could reduce injury in the diabetic heart following myocardial ischemia (MI) and reperfusion (R) by increasing the bioavailability of nitric oxide (NO). The db/db diabetic mouse exhibits obesity, hyperinsulinemia, hyperglycemia, and endothelial dysfunction similar to Type II diabetes in humans. Diabetic mice received daily injections of simvastatin (0.5 mg/kg) or vehicle for 5 days before MI-R. Simvastatin did not reduce serum cholesterol levels (105 +/- 2 mg/dl vs. 103 3 mg/dl). However, simvastatin increased eNOS mRNA levels in diabetic hearts (n=7) by 97 +/- 31% (P<0.05) compared with vehicle (n=7). Simvastatin also significantly augmented (P<0.05) vascular NO production compared with vehicle (16.0 +/- 1.6 vs. 8.9 +/- 1.5 nmol/g). Diabetic (n=12) and nondiabetic (n=10) mice were subjected to 30 min of MI and 2 h of R. Simvastatin treatment (n=11) in diabetic mice reduced (P<0.02) myocardial necrosis from 62.6 +/- 3.3 % to 37.0 +/- 6.4%. Neutrophil infiltration in the I-R myocardium was attenuated by 62% (P<0.01) in simvastatin-treated mice. Intravital microscopy demonstrated reduced leukocyte-endothelial cell interactions in simvastatin-treated diabetic mice. Thus, simvastatin attenuates injury in the diabetic myocardium by enhanced NO production without reducing cholesterol levels.