A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid

1 Recent studies have reported that hydroxymethylglutaryl coenzyme A (HMG-C oA) reductase inhibitors have vasculoprotective effects independent of thei r lipid-lowering properties, including anti-inflammatory actions. We used i ntravital microscopy of the rat mesenteric microvasculature to examine the effects of rosuvastatin, a new HMG-CoA reductase inhibitor, on leukocyte-en dothelium interactions induced by thrombin. 2 Intraperitoneal administration of 0.5 and 1.25 mg kg (1) rosuvastatin 18 h prior to the study, significantly and dose-dependently attenuated leukocy te rolling, adherence, and transmigration in the rat mesenteric microvascul ature superfused with 0.5 u ml-l thrombin. This protective effect of rosuva statin was reversed by intraperitoneal injection of 25 mg kg(-1) mevalonic acid 18 h before the study. 3 Immunohistochemical detection of the endothelial cell adhesion molecule P -selectin showed a 70% decrease in endothelial cell surface expression of P -selectin in thrombin-stimulated rats given 1.25 mg kg(-1) rosuvastatin. In addition, rosuvastatin enhanced release of nitric oxide (NO) from the vasc ular endothelium as measured directly in rat aortic segments. Moreover, ros uvastatin failed to attenuate leukocyte-endothelium interactions in peri-in testinal venules of eNOS(-) mice. 4 These data indicate that rosuvastatin exerts important anti-inflammatory effects via inhibition of endothelial cell adhesion molecule expression, an d that this protective action of rosuvastatin requires release of nitric ox ide by the vascular endothelium. These data also demonstrate that the mecha nism of the non-lipid lowering actions of HMG-CoA reductase inhibitors in v ivo may be due to reduced formation or availability of mevalonic acid withi n endothelial cells. British Journal of Pharmacology (2001).