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 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 microg per rat) was given 18 hours before study. Superfusion with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 micromol/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 microm 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 microg per rat IP) significantly attenuated L-NAME-stimulated leukocyte rolling, to 12+/-2 (P<0.01); adherence, to 5+/-0.5 leukocytes per 100 microm (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.
Pruefer
D
D
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107-6799, USA.
Scalia
R
R
Lefer
A M
AM
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001794:Blood Pressure; D002450:Cell Communication / Q000187:drug effects; D002465:Cell Movement / Q000276:immunology; D002784:Cholesterol / Q000097:blood; D004730:Endothelium, Vascular / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006490:Hemostatics / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007962:Leukocytes / Q000166:cytology* / Q000276:immunology; D008297:Male; D008642:Mesenteric Veins / Q000166:cytology / Q000276:immunology; D008853:Microscopy / Q000379:methods; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019007:P-Selectin / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D014325:Tromethamine / Q000494:pharmacology; D014657:Vasculitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D014699:Venules / Q000737:chemistry / Q000166:cytology / Q000378:metabolism
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D006490:Hemostatics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C074097:Krebs-Henseleit solution; D019007:P-Selectin; D014325:Tromethamine; D009569:Nitric Oxide; D002784:Cholesterol; D019821:Simvastatin; D013917:Thrombin; D005947:Glucose; D019331:NG-Nitroarginine Methyl Ester