Simvastatin Inhibits Leukocyte–Endothelial Cell Interactions and Protects Against Inflammatory Processes in Normocholesterolemic Rats

Abstract

Abstract —Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to lower serum cholesterol levels and normalize endothelial cell function. Moreover, HMG-CoA reductase inhibitors exert beneficial effects in coronary artery and cerebrovascular diseases. We examined the effects of simvastatin on leukocyte–endothelial cell interaction in vivo by intravital microscopy. Simvastatin (12.5 or 25 μg per rat) was given 18 hours before study. Superfusion with the NO synthase inhibitor N G -nitro- l -arginine methyl ester (L-NAME, 50 μmol/L) significantly increased leukocyte rolling from 12±2 to 60±8 leukocytes per minute, increased adherence to the mesenteric endothelium from 1.8±0.5 to 17±1.2 leukocytes per 100 μm of venular length, and raised leukocyte transmigration from 2.5±1.0 to 10±2 leukocytes per perivessel area ( P <0.01). Similar results were obtained with thrombin (0.5 U/mL) superfusion of the mesentery. In contrast, pretreatment with simvastatin (25 μg per rat IP) significantly attenuated L-NAME–stimulated leukocyte rolling, to 12±2 ( P <0.01); adherence, to 5±0.5 leukocytes per 100 μm ( P <0.01); and leukocyte transmigration, to 3.5±1.5 leukocytes per perivessel area ( P <0.01). Similar results were obtained in thrombin-superfused mesenteries. Moreover, immunohistochemical analysis demonstrated significantly increased P-selectin expression on the mesenteric venular endothelium after superfusion with either L-NAME ( P <0.01) or thrombin ( P <0.01), which was significantly attenuated by simvastatin. These results clearly demonstrate that simvastatin is a potent and effective endothelium-protective agent that reduces leukocyte–endothelial cell interactions independently of its well-known lipid-lowering effects. This effect was found to be at least partially mediated via downregulation of P-selectin expression on the microvascular endothelium. Thus, HMG-CoA reductase inhibitors like simvastatin have important anti-inflammatory effects besides their well-known lipid-lowering action.