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Enhanced responsiveness of platelets to vicagrel in IL‐10‐deficient mice through STAT3‐dependent up‐regulation of the hydrolase arylacetamide deacetylase in the intestine
Author(s) -
Jia YuMeng,
Zhou Huan,
Tai Ting,
Gu TongTong,
Ji JinZi,
Mi QiongYu,
Huang BeiBei,
Li YiFei,
Zhu Ting,
Xie HongGuang
Publication year - 2019
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.14646
Subject(s) - platelet , medicine , endocrinology , chemistry , small intestine , knockout mouse , platelet activation , pharmacology , biology , receptor
Background and Purpose Vicagrel is a novel promising antiplatelet drug designed for overcoming clopidogrel resistance. There is limited evidence indicating that exogenous IL‐10 suppresses CYP3A4 activity in healthy subjects and that IL‐10 knockout (KO) mice exhibit increased clopidogrel bioactivation compared with wild‐type (WT) mice. In this study, we sought to determine whether IL‐10 could play an important role in the metabolism of and platelet response to vicagrel in mice. Experimental Approach IL‐10 KO and WT mice were administered vicagrel, then their plasma H4 (active metabolite of vicagrel) concentrations were determined by LC–MS/MS, and inhibition of ADP‐induced whole‐blood platelet aggregation by vicagrel was assessed with an aggregometer. The mRNA and protein levels of several relevant genes between IL‐10 KO and WT mice were measured by qRT‐PCR and Western blots, respectively. Intestinal Aadac protein levels were measured in IL‐10 WT mice injected i.p. with vehicle control, Stattic, or BAY 11‐7082. Key Results Compared with WT mice, IL‐10 KO mice exhibited significantly increased plasma levels of H4 and enhanced platelet responses to vicagrel, as well as significantly higher mRNA and protein levels of arylacetamide deacetylase (Aadac) in the intestine. In WT mice, STAT3, not NF‐κB, mediated Aadac expression in the intestine. Conclusions and Implications IL‐10 suppresses metabolic activation of vicagrel through down‐regulation of Aadac in mouse intestine in a STAT3‐dependent manner and, consequently, attenuates platelet responses to vicagrel, suggesting that the antiplatelet effect of vicagrel may be modulated by changes in plasma IL‐10 levels in relevant clinical settings.