Inhibitory signaling of 17β-estradiol in platelet activation: The pivotal role of cyclic AMP-mediated nitric oxide synthase activation

Gong-Jhe Wu, Jie Jen Lee, Duen-Suey Chou, Thanasekaran Jayakumar, George Hsiao, Wei Fan Chen, Joen-Rong Sheu

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Arterial thromboses are mostly composed of platelets adherent to ruptured endothelial surfaces. Platelets are anucleated cells; therefore, they represent an excellent and unique model to selectively investigate the signaling pathways mediating the nongenomic effects of estrogen. The aim of this study was to examine the signal transduction pathways of 17β-estradiol in preventing platelet activation. In this study, 17β-estradiol (5~10μM) exhibited more-potent activity of inhibiting platelet aggregation stimulated by collagen than other agonists (i.e., thrombin). 17β-Estradiol-inhibited collagen-stimulated platelet activation accompanied by [Ca2+]i mobilization, thromboxane A2 (TxA2) formation, and phospholipase C (PLC)β2, protein kinase C (PKC), and p38 mitogen-activated protein kinase (MAPK) phosphorylation. 17β-Estradiol markedly increased cyclic AMP and cyclic GMP levels, nitric oxide (NO) release, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and endothelial nitric oxide synthase (eNOS) expression. SQ 22536, an inhibitor of adenylate cyclase, markedly reversed the 17β-estradiol-mediated effects (i.e., platelet aggregation, and PLCγ2, VASP, and eNOS phosphorylation). Furthermore, ICI 182,780, a pure estrogen receptor antagonist, also reversed the 17β-estradiol-mediated effects on platelet aggregation and eNOS activation. In conclusion, the most important findings of this study demonstrate for the first time that the inhibitory effect of 17β-estradiol in platelet activation involves activation of the cyclic AMP-eNOS/NO-cyclic GMP pathway, resulting in inhibition of PLCγ2 and p38 MAPK activation, which may lower the incidence of cardiovascular events in postmenopausal women.

Original languageEnglish
Pages (from-to)140-149
Number of pages10
JournalEuropean Journal of Pharmacology
Volume649
Issue number1-3
DOIs
Publication statusPublished - Dec 15 2010

Keywords

  • 17-γ-Estradiol
  • Cyclic AMP
  • Nitric oxide synthase
  • Phospholipase Cγ2
  • Platelet activation

ASJC Scopus subject areas

  • Pharmacology

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