髓系细胞血管紧张素1型受体在盐敏感性高血压小鼠血管胰岛素抵抗和血管损伤中的作用  

Role of myeloid angiotensin type 1 receptor in vascular insulin resistance and vascular injury in salt-sensitive hypertensive mice

作　　者：王欢 苏晓敏 杨雪峰 卓坤萍 徐茜 周明生 WANG Huan;SU Xiaomin;YANG Xuefeng;ZHUO Kunping;XU Qian;ZHOU Mingsheng(Department of Pathophysiology,Shenyang Medical College,Shenyang,Liaoning 110034,China;Department of Pathophysiology,Jinzhou Medical University,Jinzhou,Liaoning 121001,China)

机构地区：[1]沈阳医学院生理学教研室,辽宁省沈阳市110034 [2]锦州医科大学生理学教研室,辽宁省锦州市121001

出　　处：《中国动脉硬化杂志》2023年第1期41-48,共8页Chinese Journal of Arteriosclerosis

基　　金：国家自然科学基金项目(81670384、81970357);沈阳医学院科学发展基金项目(20191031);辽宁省科学技术计划项目(2019-ZD-0331);沈阳医学院大学生科研立项项目(20198025)。

摘　　要：[目的]探究髓系细胞血管紧张素1型受体(Mye AT1R)在盐敏感性高血压小鼠血管胰岛素抵抗和血管损伤中的作用。[方法]采用左肾切除和去氧皮质酮乙酸酯(DOCA)缓释药片包埋术将C57BL/6J雄性小鼠(野生型,WT)和Mye AT1R敲除小鼠(Mye AT1R^(-/-))诱导为盐敏感性高血压小鼠模型,随机分为WT组、DOCA盐敏感性高血压组(简称DOCA组)、Mye AT1R^(-/-)组和Mye AT1R^(-/-)/DOCA组,每组8只。采用尾套袖法测量小鼠收缩压,HE染色观察主动脉壁厚度,免疫荧光检测主动脉F4/80(单核/巨噬细胞标志物),RT-PCR和Western blot检测AT1R、促炎细胞因子和胰岛素信号通路分子的mRNA和蛋白表达,离体血管灌流系统测定乙酰胆碱和胰岛素介导的内皮依赖性血管舒张功能。[结果]与WT组相比,DOCA组收缩压升高37%,主动脉壁厚度增加57%,乙酰胆碱和胰岛素介导的内皮依赖性血管舒张功能分别下降32%和36%(P<0.05),主动脉F4/80阳性细胞数量增多195%,单核细胞趋化蛋白1(MCP-1)、肿瘤坏死因子α(TNF-α)、磷酸化c-Jun氨基端激酶(p-JNK)蛋白表达升高42%、45%、32%,胰岛素蛋白激酶B(Akt)/内皮型一氧化氮合酶(eNOS)信号通路受损,p-Akt和p-eNOS的蛋白表达水平下降均为36%(P<0.05)。敲除Mye AT1R,主动脉壁厚度降低14%,F4/80阳性细胞数减少44%,乙酰胆碱和胰岛素介导的内皮依赖性血管舒张功能增加21%和17%,MCP-1、TNF-α和p-JNK蛋白表达水平降低52%、41%和17%,可修复受损的胰岛素PI3K/Akt/eNOS信号通路,p-Akt和p-eNOS的蛋白表达水平升高48%和42%(P<0.05),但收缩压没有明显降低。[结论]敲除Mye AT1R可减轻盐敏感性高血压引起的血管胰岛素抵抗和血管损伤,其机制可能与抑制巨噬细胞在血管壁浸润引起的血管炎症有关。Aim To investigate the role of myeloid angiotensin type 1 receptor(Mye AT1R)in vascular insulin resistance and vascular injury in deoxycorticosterone acetate(DOCA)/salt-sensitive hypertensive mice.Methods C57BL/6J mice(wild type,WT)and Mye AT1R^(-/-)mice were randomly divided into WT group,DOCA/salt-sensitive hypertension group(DOCA group),Mye AT1R^(-/-)group and Mye AT1R^(-/-)/DOCA group,8 in each group.DOCA/saltsensitive hypertension was induced by left nephrectomy and DOCA sustained-release tablet implantation.Systolic blood pressure(SBP)was measured by tail cuff method.HE staining was used to observe aortic wall thickness,immunofluorescence was used to detect F4/80(monocyte/macrophage marker)of aorta,RT-PCR and Western blot were used for mRNA and protein expressions of AT1R,proinflammatory factors and insulin signaling molecules.Acetylcholine or insulin-induced endothelium-dependent vasodilation was determined by isolated vascular perfusion system.Results Compared with WT group,in DOCA group,systolic blood pressure increased by 37%,aortic wall thickness increased by 57%,acetylcholine or insulin-induced endothelium-dependent vasodilation decreased by 32% and 36% respectively(P<0.05),the number of F4/80 positive cells increased by 195%,the protein expression of monocyte chemoattractant protein-1(MCP-1),tumor necrosis factor-α(TNF-α)and phosphorylated c-Jun N-terminal kinase(p-JNK)were significantly increased by 42%,45% and 32% respectively,the protein expression of p-Akt and p-Enos decreased by 36% in the aorta of DOCA mice(P<0.05).Specific knockout of myeloid AT1R,aortic thickness decreased by 14%,the number of F4/80 positive cells decreased by 44%,acetylcholine or insulin-induced endothelium-dependent vasodilation improved by 21% and 17% respectively,the protein expression of MCP-1,TNF-α and p-JNK decreased by 52%,41% and 17% respectively,damaged insulin protein PI3K/Akt/eNOS signaling pathway was reversed,the protein expression of p-Akt and p-eNOS increased by 48% and 42% respectively(P<0.05)without signi

关 键 词：血管紧张素1型受体 盐敏感性高血压 胰岛素抵抗 巨噬细胞 血管损伤 

分 类 号：R3[医药卫生—基础医学] R5