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Antiplatelet activity of nifedipine is mediated by inhibition of NF‐κB activation caused by enhancement of PPAR ‐β/‐γ activity
Author(s) -
Shih ChingYu,
Lin IHsin,
Ding JamesCheng,
Chen FuChi,
Chou TzChong
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12523
Subject(s) - nifedipine , platelet activation , chemistry , pharmacology , peroxisome proliferator activated receptor , intracellular , activator (genetics) , platelet , medicine , receptor , calcium , biochemistry , biology , organic chemistry
Background and Purpose The transcription factor NF‐κB , stimulates platelet aggregation through a non‐genomic mechanism. Nifedipine, a voltage‐gated L ‐type calcium channel blocker, is widely used to treat hypertension. Nifedipine also displays antiplatelet activity, but the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiplatelet effects of nifedipine are mediated by regulating NF‐κB ‐dependent responses. Experimental Approach Platelet aggregation was measured turbidimetrically using an aggregometer. NF‐κB and PPAR activation, intracellular Ca 2+ mobilization, PKC α activity, surface glycoprotein IIb / IIIa ( GPIIb / IIIa ) expression and platelet activation‐related signalling pathways were determined in control and nifedipine‐treated platelets in the presence or absence of PPAR antagonists or betulinic acid, a NF‐κB activator. Key Results Exposure of platelets to nifedipine significantly increased the PPAR ‐β/‐γ activity in activated human platelets. Treatment with nifedipine reduced collagen‐induced NF‐κB events, including the phosphorylation of IκB kinase‐β, IκBα and p65 NF‐κB , which were markedly attenuated by GSK 0660, a PPAR ‐β antagonist, or GW 9662, a PPAR ‐γ antagonist. Furthermore, the interaction of PPAR ‐β/‐γ with NF‐κB and the PPAR ‐β/‐γ‐up‐regulated NO /c GMP / PKG1 cascade may contribute to inhibition of NF‐κB activation by nifedipine. Suppressing PPAR ‐β/‐γ activity or increasing NF‐κB activation greatly reversed the inhibitory effect of nifedipine on collagen‐induced platelet aggregation, intracellular Ca 2+ mobilization, PKC α activity and surface GPIIb / IIIa expression. Conclusions and Implications PPAR ‐β/‐γ‐dependent inhibition of NF‐κB activation contributes to the antiplatelet activity of nifedipine. These findings provide a novel mechanism underlying the beneficial effects of nifedipine on platelet hyperactivity‐related vascular and inflammatory diseases.