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Inhibition of PAR4 Signaling Mediates Ethanol‐Induced Attenuation of Platelet Function In Vitro
Author(s) -
Kasuda Shogo,
Sakurai Yoshihiko,
Shima Midori,
Morimura Yoshifumi,
Kudo Risa,
Takeda Tomohiro,
Ishitani Akiko,
Yoshioka Akira,
Hatake Katsuhiko
Publication year - 2006
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2006.00193.x
Subject(s) - chemistry , thrombin , ethanol , platelet , platelet factor 4 , platelet activation , hemostasis , pharmacology , in vitro , intracellular , calcium , biophysics , biochemistry , medicine , biology , heparin , organic chemistry
Background: Reduction in coronary heart disease morbidity in response to moderate consumption of alcoholic beverages may be partly mediated by ethanol‐induced inhibition of platelet function. However, the precise mechanisms by which ethanol modulates platelet activation induced by thrombin, which plays a central role in hemostasis, remain unclear. The goal of this study was to investigate ethanol‐induced changes in platelet function and clarify the underlying mechanisms including PAR1 and PAR4 activity and [Ca 2+ ] i dynamics in vitro. Methods: Platelet aggregation, increase in intracellular calcium ([Ca 2+ ] i ), and release of platelet factor 4 and β ‐thromboglobulin induced by α ‐thrombin, PAR1‐agonist peptide (AP), or PAR4‐AP were assessed in the presence or absence of ethanol. Results: Ethanol exposure inhibited low‐dose thrombin (0.5 nM)‐induced aggregation but not an increase in [Ca 2+ ] i . In contrast, ethanol had no effect on high‐dose thrombin (10 nM)‐induced aggregation or the [Ca 2+ ] i increase. Ethanol did not significantly inhibit thrombin‐induced release of platelet factor 4 and β ‐thromboglobulin. Ethanol reduced PAR1‐AP‐induced aggregation, but did not affect the spike form of [Ca 2+ ] i increase. In contrast, ethanol inhibited the increase in [Ca 2+ ] i as well as the aggregation in response to PAR4‐AP and resulted in delayed [Ca 2+ ] i peak time. Furthermore, ethanol inhibited both PAR1‐AP‐ and PAR4‐AP‐induced platelet factor 4 and β ‐thromboglobulin release. Conclusions: These data suggest that ethanol inhibits platelet aggregation via inhibition of PAR4 signaling and subsequent inhibition of Ca 2+ influx and granule release. This phenomenon may contribute to the reduction in coronary heart disease morbidity in response to consumption of alcoholic beverages.