Enhanced responsiveness of platelets to vicagrel in IL‐10‐deficient mice through STAT3‐dependent up‐regulation of the hydrolase arylacetamide deacetylase in the intestine

Article date: June 2019

By: Yu‐Meng Jia, Huan Zhou, Ting Tai, Tong‐Tong Gu, Jin‐Zi Ji, Qiong‐Yu Mi, Bei‐Bei Huang, Yi‐Fei Li, Ting Zhu, Hong‐Guang Xie in Volume 176, Issue 11, pages 1717-1727

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.

DOI: 10.1111/bph.14646

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