Elevations of low density lipoprotein levels are not only linked to an increased risk for athero sclerosis but may also exert prothrombotic effects via platelet activation. The effectiveness of 3 hydroxy 3 methyl glutaryl selleck bio Inhibitors,Modulators,Libraries coenzyme A reductase inhibitors in the prevention of CAD is ascribed not only to reduced cholesterol levels, but also to a number of additional effects, including the stabilization of atherosclerotic plaque, improved endothelial function, enhanced fibrinolysis, and antithrombotic effects. Although many studies have demonstrated that statins have antiplatelet activity in hypercholesterolemic patients and animals, the inhibition of platelet dependent thrombus formation in hypercholesterolemia may not correlate with the lipid lowering effects, suggesting that.

Inhibitors,Modulators,Libraries these statins may exert another effect besides from their cholesterol lowering actions. Inhibition of the thromboxane B2 formation Inhibitors,Modulators,Libraries or chang ing cholesterol content on platelet membrane by statins has been reported. Recently, Chou et al. also sug gested that enhanced nitric oxide and cyclic GMP formation of simvastatin may be involved in the inhibitory effects on platelet aggregation. The anti platelet activity of simvastatin in platelets has been stud ied. however, the detailed signal transduction mechanism by which simvastatin inhibits platelet activation Inhibitors,Modulators,Libraries has not yet been completely resolved. We therefore systematically examined the cellular signal events associated with sim vastatin inhibited platelet activation in the present study.

Methods Materials Collagen, luciferin luciferase, phorbol Inhibitors,Modulators,Libraries 12, 13 dibutyrate, 5,5 dimethyl 1 pyrroline N oxide, SQ22536, ODQ, arachidonic acid, prosta glandin E1, nitroglycerin, and thrombin were pur chased from Sigma Chem. . Fura 2 AM and fluorescein iso thiocyanate were from Molec ular Probe . the thromboxane B2 enzyme immunoassay kit was from Cayman . the anti vasodilator stimulated phosphoprotein monoclonal antibody was from Cal biochem . the anti phospho p38 mito gen activated protein kinase Ser182 mAb was from Santa Cruz . the anti p38 MAPK and anti phospho c Jun N terminal kinase mAbs, anti phospholipase C��2, anti phospho PLC��2 mAbs, and the anti phos pho p44p42 extracellular signal regulated kinase polyclonal antibody were from Cell Signaling . the anti tubulin mAb was from NeoMarkers . and the Hybond P PVDF membrane, ECL Western blotting detection reagent and analysis system, horseradish peroxidase conjugated donkey anti rabbit IgG, and Wortmannin sheep anti mouse IgG were from Amersham. Cyclic AMP and cyclic GMP EIA kits were pur chased from Cayman. Simvastatin was dissolved in 0. 5% dimethyl sulfoxide and stored at 4 C until used. Platelet aggregation Human platelet suspensions were prepared as previously described.