A new HMG‐CoA reductase inhibitor, rosuvastatin, exerts anti‐inflammatory effects on the microvascular endothelium: the role of mevalonic acid
- 1 June 2001
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 133 (3) , 406-412
- https://doi.org/10.1038/sj.bjp.0704070
Abstract
Recent studies have reported that hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have vasculoprotective effects independent of their lipid-lowering properties, including anti-inflammatory actions. We used intravital microscopy of the rat mesenteric microvasculature to examine the effects of rosuvastatin, a new HMG-CoA reductase inhibitor, on leukocyte-endothelium interactions induced by thrombin. Intraperitoneal administration of 0.5 and 1.25 mg kg(-1) rosuvastatin 18 h prior to the study, significantly and dose-dependently attenuated leukocyte rolling, adherence, and transmigration in the rat mesenteric microvasculature superfused with 0.5 u ml(-1) thrombin. This protective effect of rosuvastatin was reversed by intraperitoneal injection of 25 mg kg(-1) mevalonic acid 18 h before the study. 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 vascular endothelium as measured directly in rat aortic segments. Moreover, rosuvastatin failed to attenuate leukocyte-endothelium interactions in peri-intestinal venules of eNOS(-/-) mice. These data indicate that rosuvastatin exerts important anti-inflammatory effects via inhibition of endothelial cell adhesion molecule expression, and that this protective action of rosuvastatin requires release of nitric oxide by the vascular endothelium. These data also demonstrate that the mechanism of the non-lipid lowering actions of HMG-CoA reductase inhibitors in vivo may be due to reduced formation or availability of mevalonic acid within endothelial cells.Keywords
This publication has 27 references indexed in Scilit:
- New HMG-CoA reductase inhibitor ZD4522 lowers plasma lipids and VLDL production in APOE*3Leiden transgenic miceAtherosclerosis, 2000
- The Effect of Pravastatin on Coronary Events after Myocardial Infarction in Patients with Average Cholesterol LevelsNew England Journal of Medicine, 1996
- Prevention of Coronary Heart Disease with Pravastatin in Men with HypercholesterolemiaNew England Journal of Medicine, 1995
- Cholesterol Reduction in Cardiovascular Disease — Clinical Benefits and Possible MechanismsNew England Journal of Medicine, 1995
- Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)The Lancet, 1994
- Pharmacology of the Endothelium in Ischemia-Reperfusion and Circulatory ShockAnnual Review of Pharmacology and Toxicology, 1993
- GMP‐140: A receptor for neutrophils and monocytes on activated platelets and endotheliumJournal of Cellular Biochemistry, 1991
- Oxygen radicals induce human endothelial cells to express GMP-140 and bind neutrophils.The Journal of cell biology, 1991
- Discovery, biochemistry and biology of lovastatinThe American Journal of Cardiology, 1988
- An optical Doppler intravital velocimeterMicrovascular Research, 1984