高尿酸通过氧化应激诱导心肌细胞胰岛素抵抗  

High uric acid evokes insulin resistance via oxidative stress in cardiomyocytes

作　　者：陈映群[1] 张卫星[1] 李智 Chen Yingqun;Zhang Weixing;Li Zhi(Dept of Intensive Care Unit,Peking University Shenzhen Hospital,Shenzhen 518035)

机构地区：[1]北京大学深圳医院重症医学科,深圳518035

出　　处：《安徽医科大学学报》2022年第3期418-424,共7页Acta Universitatis Medicinalis Anhui

基　　金：广东省医学科研基金(编号:A2021059)。

摘　　要：目的探讨高尿酸对心肌细胞糖代谢、胰岛素抵抗的影响及其可能分子机制。方法将大鼠H9c2心肌细胞暴露于高尿酸环境,胰岛素刺激下荧光葡萄糖2-NBDG标记心肌细胞葡萄糖摄取,通过倒置荧光显微镜及流式细胞仪检测心肌细胞对葡萄糖的摄取及心肌细胞内活性氧生成;蛋白印迹分析检测磷酸化胰岛素受体底物1(IRS1,Ser307)和磷酸化Akt(Ser473)水平;动物模型上,检测高尿酸对胰岛素抵抗、心肌组织胰岛素信号通路相关蛋白表达的影响。结果高尿酸显著抑制心肌细胞对葡萄糖的摄取,抗氧化剂NAC可恢复心肌细胞对葡萄糖的摄取;高尿酸激活胰岛素信号通路负调节蛋白IRS1磷酸化,同时抑制心肌细胞胰岛素信号通路蛋白Akt磷酸化,这些作用可被抗氧化剂NAC阻滞。结论高尿酸通过氧化应激诱导胰岛素抵抗并抑制心肌细胞对葡萄糖摄取,为防治高尿酸相关代谢性心血管疾病提供理论依据。Objective To investigate the effect of HUA on insulin resistance in cardiomyocytes and hyperuricemic mouse model.Methods We exposed primary cardiomyocytes and a rat cardiomyocyte cell line H9c2 cardiomyocytes to HUA,then quantified glucose uptake with a fluorescent glucose analog,2-NBDG,after insulin challenge and detected reactive oxygen species(ROS)production.Western blot analysis was used to examine the levels of phosphorylated insulin receptor substrate 1(IRS1,Ser307)and phospho-Akt(Ser473).We monitored the impact of HUA on insulin resistance,insulin signaling,phospho-IRS1(Ser307)and phospho-Akt levels in myocardial tissue of an acute hyperuricemia mouse model established by potassium oxonate treatment.Results HUA inhibited insu-lin-induced glucose uptake in H9c2 cardiomyocytes.It increased ROS production,pretreatment with N-acetyl-L-cysteine(NAC),a ROS scavenger,reversed HUA-inhibited glucose uptake induced by insulin.HUA exposure directly increased the phospho-IRS1(Ser307)response to insulin and inhibited that of phospho-Akt in H9C2 cardiomyocytes,which was blocked by NAC.Furthermore,the acute hyperuricemic mice model showed impaired glucose tolerance and insulin tolerance accompanied by increased phospho-IRS1(Ser307)and inhibited phospho-Akt response to insulin in myocardial tissues.Conclusion HUA inhibits insulin signaling and induces insulin resistance in cardiomyocytes in vitro and in vivo,which is a novel potential mechanism of hyperuricemic-related cardiovascular disease.

关 键 词：高尿酸 心肌细胞 胰岛素抵抗 葡萄糖摄取 

分 类 号：R541.8[医药卫生—心血管疾病]