Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 627, Issue 1-3, Pages 85-91Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2009.11.005
Keywords
Platelet; BAY 11-7082; cAMP; TXA(2); VASP; MAP kinase
Categories
Funding
- Ministry of Commerce, Industry and Energy(MOCIE)
- Korean Institute of Industrial Technology Evaluation & Planning(ITEP), through the Biohealth Products Research Center (BPRC) of Inje University
- Ministry of Food, Agriculture, Forestry and Fisheries [20080439]
- Ministry of Knowledge Economy (MKE), Republic of Korea [B0008892] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Platelets, though anucleated, possess several transcription factors, including NF-kappa B, that exert non-genomic functions regulating platelet activation. Since platelets have not only been recognized as central players of homeostasis, but also participated in pathological conditions such as thrombosis, atherosclerosis, and inflammation, we examined rat platelet NF-kappa B expression and evaluated the effects of anti-inflammatory drug BAY 11-7082, an inhibitor of NF-kappa B activation, in platelet physiology. Western blotting revealed that rat platelets express NF-kappa B. BAY 11-7082, dose dependently, inhibited collagen- or thrombin-induced-platelet aggregation. ATP release, TXB(2) formation, P-selectin expression, and intercellular Ca(2+) concentration activated by collagen were reduced in BAY 11-7082-treated platelets. BAY 11-7082 elevated intracellular levels of cAMP, but not cGMP, and its co-incubation with cAMP-activating agent (forskolin) or its hydrolyzing enzyme inhibitor (3-isobutyl-1-methylxanthine, IBMX), synergistically inhibited collagen-induced-platelet aggregation. In addition, vasodilator-stimulated-phosphoprotein (VASP) phosphorylation was enhanced in BAY 11-7082-treated platelets, which was partially inhibited by a protein kinase A (PKA) inhibitor, H-89. Moreover, while p38 mitogen-activated protein kinase (MAPK) was not affected, BAY 11-7082 attenuated c-Jun N-terminal kinase 1 (JNK1) and extracellular-signal-regulated protein kinase 2 (ERK2) phosphorylations. In conclusion, BAY 11-7082 inhibits platelet activation, granule secretion, and aggregation, and that this effect is mediated by inhibition of JNK1 and ERK2 phosphorylations, and partially by stimulation of cAMP-dependent PKA VASP phosphorylation. The ability of BAY 11-7082 to inhibit platelet function might be relevant in cases involving aberrant platelet activation where the drug is considered as anti-atherothrombosis, and anti-inflammatory therapy. (C) 2009 Elsevier B.V. All rights reserved.
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