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摘要:OBJECTIVE Transient receptor potential melastatin-2(TRPM2) is a nonselective cation channel mediating Ca2+influx in response to oxidative stress. Given that insulin resistance-related endothelial dysfunction in obesity attributes to fatty-acid-induced reactive oxygen species(ROS) overproduction, in this study, we addressed the possible role of TRPM2 in obesity-related endothelial insulin resistance and the underlying mechanisms.METHODS Whole-cell patch clamp technique, intracellular Ca2+concentration measurement, Western blotting, vasorelaxation assay, and high-fat diet(HFD)-induced obese model were employed to assess the relationship between TRPM2 and endothelial insulin response. RESULTS We found that both the expression and activity of TRPM2 were higher in endothelial cells of obese mice. Palmitate rose a cationic current in endothelial cells which was inhibited or enlarged by TRPM2 knockdown or overexpression. Silencing of TRPM2 remarkably improved insulininduced endothelial Akt activation, nitric oxide synthase(eNOS) phosphorylation and nitric oxide(NO) production, while TRPM2 overexpression resulted in the opposite effects. Furthermore, TRPM2-mediated Ca2 +entry,CaMKII activation and the followingactivation of PERK/ATF4/TRB3 cascade were involved in the mechanism of obesity or palmitate-induced endothelial insulin resistance. Notably, in vivo study, knockdown of TRPM2 with adeno-associated virus harboring short-hairpin RNA(shRNA) against TRPM2 alleviated endothelial insulin resistance and ameliorated endothelium-dependent vasodilatation in obese mice. CONCLUSION TRPM2-activated Ca2 +signaling is necessary to induceinsulin resistancerelated endothelial dysfunction in obesity. Downregulation or pharmacological inhibition of TRPM2 channels may lead to the development of effective drugs for treatment of endothelial dysfunction associated with oxidative stress state.
会议名称:

中国药理学会第十五次全国学术大会

会议时间:

2019-11-10

会议地点:

中国北京

  • 专辑:

    医药卫生科技

  • 专题:

    内分泌腺及全身性疾病

  • DOI:

    10.26914/c.cnkihy.2019.070086

  • 分类号:

    R589.2

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