Toll样受体4-可能参与高血压左室重构的一个新的跨膜信号转导受体(英文)

Toll like receptor 4-a potential transmembrane receptor contributes to the cardiac remodeling of hypertension

目的:观察Goldblatt大鼠左室重构过程中TLR4表达及其与压力负荷及左室心肌血管紧张素Ⅱ含量的相互关系,探讨TLR4在高血压左室重构发生发展中的作用及参与机制。方法:健康雄性Sprague-Dawley(SD)大鼠7-9周龄,体重165-210 g。采用2肾一夹法建立Goldblatt大鼠模型,45只SD大鼠随机分为高血压组(H组,n=25)和假手术组(Sham组,n=20)。每周测1次尾动脉压,每2周测1次超声心动图,术后第8周,处死大鼠,留取左室心肌组织。免疫组化观察左室心肌TLR4表达,应用RT-PCR及Western blotting从mRNA及蛋白水平检测TLR4的表达情况;放免检测左室心肌AngⅡ的含量。结果:术后8周H组尾动脉压、收缩末期经线室壁应力(MESS)及左室重量指数(LVMI)、相对室壁厚度(RWT)和心肌AngⅡ含量均明显高于sham组(P<0.01);H组大鼠左室心肌组织中TLR4 mRNA及蛋白表达水平均明显高于sham组(P<0.01);免疫组化发现TLR4的表达,H组主要是在心肌细胞膜,尤其2个或2个以上的心肌细胞相邻处有团簇样表达,但也有半数样本的胞浆内有少量表达;正常对照组主要弥漫表达于胞浆内,胞膜的表达极少。相关性分析TLR4蛋白表达与反应左室重构的LVMI、RWT呈正相关(r=0.614,P<0.01;r=0.621,P<0.01);同时与反应压力负荷的尾动脉压、MESS及局部AngⅡ含量相关。结论:Goldblatt大鼠左室重构过程中TLR4 mRNA及蛋白水平均明显增加,增强表达的TLR4主要位于心肌细胞膜,尤其2个或2个以上的心肌细胞相邻处有团簇样表达。提示TLR4这一与免疫炎症密切相关的跨膜信号转导受体及其介导的信号通路可能参与高血压左室重构的发生发展。

AIM ： To observe the expression of Toll like receptor 4 （TLR4） in the left ventricle of Goldblatt rats and to explore the role and mechanism of TLR4 in left ventricular remodeling of hypertension. METHODS： Goldblatt model of Two - kidney, one - clip（2K1C） renovascular hypertension was induced in twenty - five rats（ H group） , and twenty rats served the sham -operated group（ sham group）. The tail cuff blood pressure was detected every week and echocardiogram was observed every other week. After eight weeks of operation, the rats were killed and the samples of the left ventricle were collected. The concentration of Ang Ⅱ in left ventricle was assessed by radioimmunoassay. Western blotting and RT - PCR were used to exam the mRNA and protein expression of TLR4 in the left ventricle. Immunohistochemistry was adopted to exam the location of TLR4 in the myocardium. RESULTS ： TLR4 mRNA and protein expression were consistently upregulated in the left ventricle of H group compared with sham group. In H group, predominantly sarcolemmal staining was observed, especially focal areas of intense TLR4 staining were found in juxtaposed regions of two or more adjacent myocytes; However, in sham group, TLR4 expression was diffuse and presumably cytoplasmic. Considerable correlation was found between blood pressure, MESS, LVMI, RWT, the concentration of Ang Ⅱ in left ventricle and the protein expression of TLR4 in myocytes. CONCLUSION ： During the development of left ventricular remodeling of Goldblatt rats, expression of TLR4 increases significantly. Enhanced expression of TLR4 locates in the sarcolemma, especially in juxtaposed regions of two or more adjacent myocytes. These indicate that TLR4 transmembrane receptor which is closely relative with inflammation and immunity probably contributes to the development of ventricular remodeling.