Simvastatin Exerts Both Anti-inflammatory and Cardioprotective Effects in Apolipoprotein E–Deficient Mice

Abstract

Background —Simvastatin attenuates ischemia and reperfusion in normocholesterolemic animals by stabilizing endothelial nitric oxide synthase activity and inhibiting neutrophil-mediated injury. Because endothelial dysfunction is a detrimental effect of hypercholesterolemia, we examined whether short-term treatment with simvastatin could inhibit leukocyte-endothelium interaction and attenuate myocardial ischemia-reperfusion injury in apoE-deficient (apoE –/– ) mice fed a high-cholesterol diet. Methods and Results —We studied leukocyte-endothelium interactions in apoE –/– mice fed a normal or a high-cholesterol diet after short-term (ie, 18 hours) simvastatin treatment. We also studied simvastatin treatment in myocardial ischemia-reperfusion injury by subjecting apoE –/– mice to 30 minutes of ischemia and 24 hours of reperfusion. ApoE –/– mice fed a high-cholesterol diet exhibited higher blood cholesterol levels, which were not affected by short-term simvastatin treatment. However, the increased leukocyte rolling and adherence that occurred in cholesterol-fed apoE –/– mice ( P <0.001 versus control diet) were significantly attenuated by simvastatin treatment ( P <0.01 versus vehicle). Cholesterol-fed apoE –/– mice subjected to myocardial ischemia-reperfusion also experienced increased myocardial necrosis ( P <0.01 versus control diet), which was significantly attenuated by simvastatin ( P <0.01 versus vehicle). Simvastatin therapy also significantly increased vascular nitric oxide production in apoE –/– mice. Conclusions —Simvastatin attenuates leukocyte-endothelial cell interactions and ameliorates ischemic injury in hypercholesterolemic mice independently of lipid-lowering actions.