Abstract
Background3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been widely used to reduce cardiovascular risk. These statins (i.e., simvastatin) may exert other effects besides from their cholesterol-lowering actions, including inhibition of platelet activation. Platelet activation is relevant to a variety of coronary heart diseases. Although the inhibitory effect of simvastatin in platelet activation has been studied; the detailed signal transductions by which simvastatin inhibit platelet activation has not yet been completely resolved.MethodsThe aim of this study was to systematically examine the detailed mechanisms of simvastatin in preventing platelet activation. Platelet aggregation, flow cytometric analysis, immunoblotting, and electron spin resonance studies were used to assess the antiplatelet activity of simvastatin.ResultsSimvastatin (20-50 μM) exhibited more-potent activity of inhibiting platelet aggregation stimulated by collagen than other agonists (i.e., thrombin). Simvastatin inhibited collagen-stimulated platelet activation accompanied by [Ca2+]i mobilization, thromboxane A2 (TxA2) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC), and mitogen-activated protein kinases (i.e., p38 MAPK, JNKs) phosphorylation in washed platelets. Simvastatin obviously increased both cyclic AMP and cyclic GMP levels. Simvastatin markedly increased NO release, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and endothelial nitric oxide synthase (eNOS) expression. SQ22536, an inhibitor of adenylate cyclase, markedly reversed the simvastatin-mediated inhibitory effects on platelet aggregation, PLCγ2 and p38 MAPK phosphorylation, and simvastatin-mediated stimulatory effects on VASP and eNOS phosphorylation.ConclusionThe most important findings of this study demonstrate for the first time that inhibitory effect of simvastatin in platelet activation may involve activation of the cyclic AMP-eNOS/NO-cyclic GMP pathway, resulting in inhibition of the PLCγ2-PKC-p38 MAPK-TxA2 cascade, and finally inhibition of platelet aggregation.
Highlights
A high incidence of atherosclerosis and thrombotic complications has been associated with hypercholesterolemia
Effects of simvastatin on platelet aggregation, αIIbβ3 integrin conformational change, and [Ca2+]i mobilization in human platelets Simvastatin (20-70 μM) exhibited potent activity of inhibiting platelet aggregation and the ATP-release reaction stimulated by collagen (1 μg/ml, open circle)
The IC50 value of simvastatin for platelet aggregation induced by collagen was approximately 30 μM
Summary
A high incidence of atherosclerosis and thrombotic complications has been associated with hypercholesterolemia. Elevations of low-density lipoprotein (LDL) levels are linked to an increased risk for atherosclerosis but may exert prothrombotic effects via these statins may exert another effect besides from their cholesterol-lowering actions. Inhibition of the thromboxane B2 formation or changing cholesterol content on platelet membrane by statins has been reported [7,8]. Chou et al [6] suggested that enhanced nitric oxide (NO) and cyclic GMP formation of simvastatin (20-80 μM) may be involved in the inhibitory effects on platelet aggregation. The antiplatelet activity of simvastatin in platelets has been studied; the detailed signal transduction mechanism by which simvastatin inhibits platelet activation has not yet been completely resolved. We systematically examined the cellular signal events associated with simvastatin-inhibited platelet activation in the present study
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