Rho激酶信号通路在两肾一夹肾性高血压大鼠心肌肥大中的作用及Fasudil干预

目的: 了解Rho激酶介导的信号转导通路在两肾一夹(two-kidneys-one-clip,2K1C)肾性高血压大鼠心肌肥大发病机制中的作用以及特异性Rho激酶抑制剂Fasudil干预效应。方法: 制备两肾一夹肾性高血压大鼠模型,实验设假手术组、模型组、实验组(Fasudi l10 mg·kg^-1·d^-1腹腔注射)。电子天平称量左心室质量并计算左心室质量与体质量比值;光学显微镜观察心肌组织形态学变化;Western blotting检测肌球蛋白结合亚基磷酸化(phosphorylation of myosin-binding submet,MBS-P)表达作为Rho激酶功能活化标志;RT-PCR检测Rho激酶mRNA表达。结果: 术后12周,模型组大鼠出现较显著的心肌肥大(P<0.01),心肌组织Rho激酶活性及mRNA表达显著增加(P<0.01)且Rho激酶活性及mRNA表达与心肌肥大程度间呈显著正相关(P<0.05)。Rho激酶特异性抑制剂Fasudil在抑制大鼠心肌组织Rho激酶活化和mRNA表达的同时可有效抑制心肌肥大的发展(P<0.01)。结论: Rho激酶介导的信号转导通路在2K1C肾性高血压大鼠心肌肥大发病机制中可能具有重要作用,Rho激酶特异性抑制剂Fasudil可有效抑制心肌肥大的发展。

Role of Rho-kinase signal pathway on myocardium hypertrophy of 2K1C renal hypertension rats and effects of Fasudil

AIM: To investigate the role of Rhokinase mediated signal pathway on myocardium hypertrophy of two-kidneys-one-clip (2K1C) renal hypertension rats and effects of fasudil.METHODS: 2K1C renal hypertensive model was established in Sprague-Dawley rats by chronic partial occlusion of left renal artery.The rats were randomly divided into 3 groups: Sham Group, Model Group, Experimental Group(Fasudil 10mg·kg^-1·d^-1, intraperitoneal injection).Left ventricular mass and left ventricular mass to body mass ratio were measured with electronic balance.Myocardial histomorphology was observed by light microscope. The extent of phosphorylation of myosin-binding submet (MBS-P) of myosin phosphatase was quantified by western blotting analysis, and it was used to evaluate the activity of Rho-kinase.The expression of Rho-kinase mRNA was examined by RT-PCR analysis.RESULTS: At 12th week after renovascular constriction, there was noticeable myocardial hypertrophy in Model Group(P<0.01).The Rho-kinase activity and Rho-kinase mRNA expression were significantly increased in Model Group(P<0.01).There was a positive correlation between Rho-kinase activity and myocardial hypertrophy (P<0.05), and there was a positive correlation between Rho-kinase mRNA expression and myocardial hypertrophy in Model Group(P<0.05).Fasudil-a Rho-kinase specific inhibitor, effectively inhibited myocardial hypertrophy and prevented changes of Rho-kinase activity and mRNA expression in renal hypertension rats (P<0.01).CONCLUSION: The Rho-kinase mediated signal pathway may play an important role in the development of myocardial hypertrophy in 2K1C renal hypertension rats.