HMG-CoA reductase inhibitor attenuates platelet adhesion in intestinal venules of hypercholesterolemic mice.
Whereas the anti-inflammatory properties of statins have been extensively studied, less attention has been devoted to the antithrombogenic effects of these drugs. We evaluated the effect of short-term (18 h) treatment with pravastatin (1 mg/kg) on hypercholesterolemia-induced platelet-endothelial (P/E) cell adhesion in intestinal venules. Mice were placed on either a normal diet (ND) or cholesterol-enriched diet (HCD) for 2 wk. Wild-type mice fed a HCD exhibited significantly elevated blood serum cholesterol levels, which were unaltered by pravastatin treatment. ND or HCD platelets were isolated, fluorescently labeled, and administered to either ND or HCD recipients. Intravital videomicroscopy was used to quantify transient (saltation) and firm adhesion of platelets. HCD mice receiving platelets from either ND or HCD mice exhibited increased P/E cell interactions compared with ND mice receiving platelets from ND or HCD mice. P/E adhesion was dramatically reduced when platelets from donor mice, recipient mice, or both were treated with pravastatin. The protective effect of pravastatin in hypercholesterolemia-induced P/E cell adhesion was abolished in N(G)-nitro-l-arginine methyl ester-treated mice. These results indicate that 1). hypercholesterolemia-induced P/E cell adhesion is mediated by changes in the vascular wall rather than circulating platelets; 2). pravastatin treatment inhibits the prothrombogenic effects of hypercholesterolemia via an action on both endothelial cells and platelets; and 3). the protective effect of pravastatin is nitric oxide dependent.
Tailor
Anitaben
A
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3982, USA.
Lefer
David J
DJ
Granger
D Neil
DN
D000818:Animals; D002784:Cholesterol / Q000097:blood; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000097:blood*; D007422:Intestines / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010973:Platelet Adhesiveness / Q000187:drug effects*; D017035:Pravastatin / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014699:Venules / Q000378:metabolism
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009569:Nitric Oxide; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017035:Pravastatin; D019331:NG-Nitroarginine Methyl Ester