Effects of peroxisome proliferator-activated receptor 纬 in simvastatin antiplatelet activity: Influences on cAMP and mitogen-activated protein kinases

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• 作者：Hong Du^a ; Haijuan Hu^a ; Hongmei Zheng^a ; Jie Hao^a ; Jingci Yang^b ; Wei Cui^a ; ^{cuiwei@medmail.com.cn" class="auth_mail}
• 关键词：PPARs ; peroxisome proliferator-activated receptors ; cAMP ; cyclic adenosine monophosphate ; VASP ; vasodilator-stimulated phosphoprotein ; MAPKs ; mitogen-activated protein kinases ; ERK ; extracellular signal-regulated kinase ; JNK ; c-Jun N-terminal kinase ; LDL ; low-density lipoprotein ; HMG-CoA ; 3-hydroxymethyl-3-methylglutaryl coenzyme A ; PGE1 ; prostaglandin E1
• 刊名：Thrombosis Research
• 出版年：July 2014
• 年：2014
• 卷：134
• 期：1
• 页码：111-120
• 全文大小：1350 K

文摘

Statins are widely used as hypolipidemic drugs, and have beneficial effects in reducing cardiovascular events. In addition, recent studies on the pleiotropic effects of statins (i.e., simvastatin) reveal that these drugs have many additional anti-atherogenic effects, including antiplatelet activity. The mechanisms may be partly related to activation of peroxisome proliferator-activated receptors (PPARs), which are present in human platelets, and whose activation inhibits platelet aggregation. However, the details of the signaling pathway by which simvastatin inhibits platelet activation via PPARs have not yet been completely established. The aim of this study was to examine the mechanisms by which the PPAR-mediated pathways contribute to the antiplatelet activity of simvastatin. Simvastatin (3-50 渭M) induced PPAR伪 and PPAR纬 activation in a dose-dependent manner in washed platelets. Additionally, simvastatin inhibited collagen-induced platelet aggregation, expression of CD62 and PAC-1, and Ca^2 + mobilization. These effects of simvastatin on platelet responses were strongly reduced by adding a selective PPAR纬 antagonist (GW9662), but not PPAR伪 antagonist (GW6471). Moreover, in the presence of GW9662, simvastatin-mediated increase of cyclic adenosine monophosphate (cAMP) production, vasodilator-stimulated phosphoprotein (VASP) Ser¹⁵⁷ phosphorylation and inhibition of Akt phosphorylation were markedly reversed. Furthermore, simvastatin was found to inhibit phosphorylation of mitogen-activated protein kinases (MAPKs, i.e., p38 MAPK, ERK) by increasing the association between PPAR纬 and the components of MAPKs after platelet activation. Taken together, the present results confirm that simvastatin inhibition of platelet activation is mediated by PPAR纬-dependent processes, which involves mediating MAPKs signaling, increase of cAMP formation and VASP Ser¹⁵⁷ phosphorylation, inhibition of Akt phosphorylation and intracellular Ca^2 + mobilization.