title: Effects of peroxisome proliferator-activated receptor γ in simvastatin antiplatelet activity: influences on cAMP and mitogen-activated protein kinases.
abstract: 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 μM) induced PPARα and PPARγ 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 PPARγ antagonist (GW9662), but not PPARα antagonist (GW6471). Moreover, in the presence of GW9662, simvastatin-mediated increase of cyclic adenosine monophosphate (cAMP) production, vasodilator-stimulated phosphoprotein (VASP) Ser(157) 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 PPARγ and the components of MAPKs after platelet activation. Taken together, the present results confirm that simvastatin inhibition of platelet activation is mediated by PPARγ-dependent processes, which involves mediating MAPKs signaling, increase of cAMP formation and VASP Ser(157) phosphorylation, inhibition of Akt phosphorylation and intracellular Ca(2+) mobilization.
authors.affiliation: Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.affiliation: Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei.
authors.forename: Haijuan
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei.
authors.forename: Jie
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Hematology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei.
authors.forename: Jingci
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei. Electronic address: cuiwei@medmail.com.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism; D003324:Coronary Artery Disease / Q000188:drug therapy*; D000242:Cyclic AMP / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D000924:Anticholesteremic Agents; D047495:PPAR gamma; D019821:Simvastatin; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases
keywords: Cyclic adenosine monophosphate; Mitogen-activated protein kinase; Peroxisome proliferator-activated receptor; Platelet activation; Simvastatin; Statin