Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats

Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in hibitor, has been shown to lower serum cholesterol levels and normalize end othelial cell function. Moreover, HMG-CoA reductase inhibitors exert benefi cial effects in coronary artery and cerebrovascular diseases. We examined t he effects of simvastatin on leukocyte-endothelial cell interaction in vivo by intravital microscopy. Simvastatin (12.5 or 25 mu g per rat) was given 18 hours before study. Superfusion with the NO synthase inhibitor N-G-nitro -L-arginine methyl ester (L-NAME, 50 mu mol/L) significantly increased leuk ocyte rolling from 12+/-2 to 60+/-8 leukocytes per minute, increased adhere nce to the mesenteric endothelium from 1.8+/-0.5 to 17+/-1.2 leukocytes per 100 mu m of venular length, and raised leukocyte transmigration from 2.5+/ -1.0 to 10+/-2 leukocytes per perivessel area (P<0.01). Similar results wer e obtained with thrombin (0.5 U/mL) superfusion of the mesentery. In contra st, pretreatment with simvastatin (25 mu g per rat IF) significantly attenu ated L-NAME-stimulated leukocyte rolling, to 12+/-2 (P<0.01); adherence, to 5+/-0.5 leukocytes per 100 mu m (P<0.01); and leukocyte transmigration, to 3.5+/-1.5 leukocytes per perivessel area (P<0.01). Similar results were ob tained in thrombin-superfused mesenteries. Moreover, immunohistochemical an alysis demonstrated significantly increased P-selectin expression on the me senteric venular endothelium after superfusion with either L-NAME (P<0.01) or thrombin (P<0.01), which was significantly attenuated by simvastatin. Th ese results clearly demonstrate that simvastatin is a potent and effective endothelium-protective agent that reduces leukocyte-endothelial cell intera ctions independently of its well-known lipid-lowering effects. This effect was found to be at least partially mediated via downregulation of P-selecti n expression on the microvascular endothelium. Thus, HMG-CoA reductase inhi bitors like simvastatin have important anti-inflammatory effects besides th eir well-known lipid-lowering action.