Cyclic nucleotides and mitogen-activated protein kinases: regulation of simvastatin in platelet activation

Journal of Biomedical Science

Research

Jie-Jen Lee¹  Duen-Suey Chou¹  George Hsiao¹  Joen-Rong Sheu²  Ye-Ming Lee³  Wei-Fan Chen⁴  Ssu-Yu Hou⁴  Thanasekaran Jayakumar⁴ 

[1] Department of Pharmacology, Taipei Medical University, Taipei, Taiwan;Department of Pharmacology, Taipei Medical University, Taipei, Taiwan;Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan;Department of Surgery, Hsinchu Mackay Memorial Hospital, Hsinchu; Mackay Medicine, Nursing and Management College, Taipei, Taiwan;Department of Pharmacology, Taipei Medical University, Taipei, Taiwan;Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan;

关键词: Electron Spin Resonance;    Simvastatin;    Platelet Aggregation;    Inhibit Platelet Aggregation;    Platelet Suspension;   

DOI  :  10.1186/1423-0127-17-45

 received in 2010-01-18, accepted in 2010-06-04,  发布年份 2010

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Lee et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.