A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid.
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.
Stalker
T J
TJ
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, PA, USA.
Lefer
A M
AM
Scalia
R
R
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005464:Fluorobenzenes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017353:Gene Deletion; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007082:Ileum / Q000098:blood supply; D066298:In Vitro Techniques; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D019007:P-Selectin / Q000378:metabolism; D011743:Pyrimidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068718:Rosuvastatin Calcium; D013152:Splanchnic Circulation / Q000187:drug effects; D013449:Sulfonamides; D013917:Thrombin / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019007:P-Selectin; D011743:Pyrimidines; D013449:Sulfonamides; D009569:Nitric Oxide; D000068718:Rosuvastatin Calcium; D019001:Nitric Oxide Synthase; D013917:Thrombin; D008798:Mevalonic Acid