小凹蛋白-1介导阿托伐他汀对自发性高血压大鼠肾叶间动脉收缩反应的抑制作用  

Inhibitory effects of Caveolin-1-m ediated atorvastatin on vasoconstriction of interlobar renal artery in SHR rats

作　　者：谢小萍[1] 张海军[1] 郭艺彬 张茜[1] 常耀明[1] 暴军香[1] 

机构地区：[1]第四军医大学航空航天卫生学教研室,西安710032

出　　处：《临床肾脏病杂志》2017年第10期624-630,共7页Journal Of Clinical Nephrology

基　　金：国家自然科学基金项目资助(No.81401550;81671856)

摘　　要：目的肾叶间动脉收缩反应增强是高血压肾脏损伤的早期表现,是重要的预防和治疗靶点。平滑肌细胞小凹蛋白-1(caveolin-1)上调是其发生机制之一,阿托伐他汀(atorvastatin,ATVS)可通过降低胆固醇(cholesterol,CHO)调控caveolin-1表达,本研究探讨ATVS是否通过caveolin-1抑制自发性高血压大鼠(spontaneously hypertensive rat,SHR)肾叶间动脉对血管紧张素II(angiotensin,Ang II)的收缩反应。方法 12只SHR大鼠随机分为2组:SHR对照组及ATVS(50 mg·kg^(-1)·d^(-1))处理组,每组6只,6只Wistar Kyoto(WKY)大鼠作为正常对照组。采用尾套法测量大鼠尾动脉收缩压(systolic blood pressure,SBP),血管环张力描记技术检测肾叶间动脉收缩反应,蛋白免疫印迹(Western blot)法检测caveolin-1和血管紧张素Ⅱ1型受体(angiotensin II type 1 receptor,AT1)蛋白表达,免疫沉淀和Western blot检测caveoin-1与AT1的结合。结果与WKY大鼠相比,SHR组SBP显著增高(P<0.05),肾叶间动脉对AngⅡ的收缩反应强度及敏感性均显著增强(P<0.05);4周ATVS处理显著降低SHR组SBP(P<0.05)及肾叶间动脉对AngⅡ的收缩反应强度及敏感性(P<0.05)。SHR组动脉AT1及caveolin-1的蛋白表达显著高于WKY大鼠(P<0.05),AngⅡ孵育所致caveolin-1与AT1的结合亦较WKY组显著增多(P<0.05)。ATVS处理可降低SHR组caveolin-1和AT1的蛋白表达(P<0.05),并抑制caveolin-1与AT1的结合(P<0.05),CHO孵育则可增高ATVS组caveolin-1蛋白含量并促进其与AT1的相互作用(P<0.05),同时可显著增加肾叶间动脉对AngⅡ收缩反应的强度及敏感性(P<0.05)。结论 ATVS可抑制SHR大鼠肾叶间动脉对AngⅡ的收缩反应,其机制与caveolin-1的蛋白表达降低及caveolin-1与AT1的结合减少有关。Objective Excessive vasoconstriction of interlobar renal artery（ IRA） is one of preliminary manifestations of renal damage in hypertension,during which caveolin-1 plays an important role. Atorvastatin（ ATVS） represses cholesterol（ CHO） synthesis to down-regulate the expression of caveolin-1,so we aimed to investigate whether the ATVS inhibited vasoconstriction of IRA to angiotensinⅡ（ Ang Ⅱ） by regulating caveolin-1 in spontaneously hypertensive rats（ SHR）. Methods Twelve SHR were randomly divided into two groups： SHR control group,and SHR ATVS-treated group. Six Wistar Kyoto（ WKY） rats weighing the same were employed as control group. Systolic blood pressure（ SBP） was measured with the tail-cuff technique before and 2 or 4 weeks after ATVS treatment. Isometric force recording system was used to detect the vascular function. Western blotting was conducted toexamine the protein abundance of caveolin-1 or angiotensin Ⅱ type 1 receptor（ AT1）. Immumoprecipitation was carried out to assess the binding of caveolin-1 and AT1. Results SBP,and intensity and sensitivity of vasoconstriction of IRA to Ang Ⅱ were significantly increased in SHR as compared to WKY rats（ P〈0. 05）. At 4 th week,ATVS treatment could significantly reduce SPB（ P〈0. 05）,and the intensity and sensitivity of vasoconstriction of IRA to Ang Ⅱ（ P〈0. 05） in SHR control group. Meanwhile,the protein expression of caveolin-1 or AT1 as well as Ang Ⅱ elicited binding of caveolin-1 or AT1 in IRA was higher in SHR than in WKY rats,which could also be reduced by ATVS（ P〈0. 05）.The ex vivo incubation of CHO raised the caveolin-1 protein content and promoted the binding of caveolin-1 and AT1 in IRA of ATVS-treated SHR（ P〈0. 05）. At the same time,CHO enhanced the intensity and sensitivity of vasoconstriction of IRA to Ang Ⅱ（ P〈0. 05）. Conclusions ATVS mitigated the vasoconstriction of IRA to Ang Ⅱ in SHR,which was mediated by reducing caveolin-1 expression and inhibiting the binding

关 键 词：阿托伐他汀 高血压 血管紧张素Ⅱ 小凹蛋白-1 

分 类 号：R544.1[医药卫生—心血管疾病]