Mechanisms of antiplatelet activity of nifedipine: role of peroxisome proliferator-activated receptor-β-γ-dependent processes.

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Title:	Mechanisms of antiplatelet activity of nifedipine: role of peroxisome proliferator-activated receptor-β-γ-dependent processes.
Authors:	施靖瑜;Shih, CY;林明賢;Lin, MH;范洪春;Fan, HC;陳福基;Chen, FC;周志中;*, Tz-Chong Chou
Contributors:	生物科技學系
Date:	2014-03
Issue Date:	2014-07-03 07:42:13 (UTC+0)
Abstract:	OBJECTIVE: Nifedipine, an L-type calcium channel blocker, is widely used in the treatment of hypertension and coronary heart diseases, and also exhibits an antiplatelet activity. Activation of peroxisome proliferator-activated receptors (PPARs; α, β/δ, and γ) inhibits the platelet aggregation. Therefore, the purpose of this study was to evaluate the contribution of PPAR-mediated processes to the antiplatelet activity of nifedipine. METHODS AND RESULTS: We assessed human platelet aggregation by using an aggregometer and measured several platelet activating markers and related signaling pathways in platelets treated with nifedipine in the presence or absence of PPAR agonists. Nifedipine treatment (1, 5 μmol/l) dose-dependently increased the activity and intracellular expression of PPAR-β/-γ by inhibiting the release of PPAR-β/-γ from activated platelets. Nifedipine treatment also upregulated cyclic 3',5'-cyclic monophosphate (GMP)/protein kinase G (PKG) expression, and increased PI(3)K/Akt pathway, endothelial nitric oxide synthase, and soluble guanylyl cyclase activities. In the presence of a selective PPAR-β antagonist (GSK0660) or PPAR-γ antagonist (GW9662), the inhibitory effects of nifedipine on collagen-induced platelet aggregation, intracellular Ca mobilization, and protein kinase C (PKC-α) activation were abrogated. Similarly, PPAR-β-γ antagonists markedly attenuated nifedipine-mediated upregulation of nitric oxide/cyclic GMP/PKG cascade. In a mouse model of thrombosis, the administration of nifedipine substantially inhibited fluorescein sodium-induced vessel thrombus formation; however, the antithrombotic effect was considerably reduced in the presence of PPAR-β/-γ antagonists. CONCLUSION: This study is the first to show that the PPAR-β/-γ-dependent upregulation of PI(3)K/Akt/nitric oxide/cyclic GMP/PKG pathway and the inhibition of PKC-α activity and intracellular Ca(+) mobilization in platelets may be the mechanisms underlying the antiplatelet and antithrombotic activities of nifedipine.
Relation:	JOURNAL OF HYPERTENSION;32(1):181-92.
Appears in Collections:	[Department of Biotechnology] Journal Article

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