The present study aims to study the role of receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin (RANKL/RANK/OPG) system in cardiac hypertrophy in a spontaneous hypertension rat (SHR) model and the effects of amlodipine and atorvastatin intervention. Thirty-six-week-old male SHRs were randomly divided into four groups: 1) SHR control group; 2) amlodipine alone (10 mg/kg/d) group, 3) atorvastatin alone (10 mg/kg/d) group, 4) combination of amlodinpine and atorvastatin (10 mg/kg/d for each) group. Same gender, weight, and age of Wistar-Kyoto (WKY) rats with normal blood pressure were used as normal control. Drugs were administered by oral gavage over 12 weeks. The thicknesses of left ventricle walls, left ventricle weight, and cardiac function were measured by transthoracic echocardiography. Left ventricular pressure and function were assessed by hemodynamic examination. Cardiomyocyte hypertrophy and collagen accumulation in cardiac tissue were measured by hematoxylin and eosin (HE) and Masson staining, respectively. The hydroxyproline content of cardiac tissue was examined by biochemistry technique. RANKL, RANK and OPG mRNA, protein expression and tissue localization were studied by RT-PCR, Immunohistochemistry and Western blot. Treatment with amlodipine or atorvastatin alone significantly decreased left ventricular mass index, cardiomyocyte cross-sectional area and interstitial fibrosis in SHR (each P < 0.05). Moreover, combined amlodipine and atorvastatin treatment induced significant reversal of left ventricular hypertrophy and decreased cardiomyocyte cross-sectional area and interstitial fibrosis in SHR to a greater extent than each agent alone (P < 0.05). Compared with WKY rats, the myocardial expression of RANKL, RANK, and OPG was increased. Both amlodipine and atorvastatin reduced RANKL, RANK, and OPG expression, with the best effects seen with the combination. Based on our results, activation of the RANKL/RANK/OPG system may be an important factor leading to ventricular remodeling in SHR rats. Amlodipine and atorvastatin could improve ventricular remodeling in SHR rats through intervention with the RANKL/RANK/OPG system.

译文

本研究旨在研究核因子 κ B受体激活剂配体/核因子 κ B受体激活剂/骨保护素 (RANKL/RANK/OPG) 系统在自发性高血压大鼠 (SHR) 模型中心肌肥大的作用以及氨氯地平和阿托伐他汀的干预作用。36周龄男性SHR随机分为四组: 1) SHR对照组; 2) 氨氯地平单用 (10  mg/kg/d) 组,3) 阿托伐他汀单用 (10  mg/kg/d) 组,4) 氨氯地平联合阿托伐他汀 (10  mg/kg/d) 组。将血压正常的Wistar-Kyoto (WKY) 大鼠的相同性别,体重和年龄用作正常对照。在12周内通过口服灌胃给药。通过经胸超声心动图测量左心室壁的厚度,左心室重量和心功能。通过血流动力学检查评估左心室压力和功能。分别用苏木精和曙红 (HE) 和Masson染色测量心肌细胞肥大和心肌组织中胶原蛋白的积累。通过生化技术检查心脏组织中的羟脯氨酸含量。通过rt-pcr,免疫组织化学和Western blot研究RANKL,RANK和OPG mRNA,蛋白质表达和组织定位。单独使用氨氯地平或阿托伐他汀可显着降低SHR的左心室质量指数,心肌细胞横截面积和间质纤维化 (各p  <  0.05)。此外,氨氯地平和阿托伐他汀联合治疗可显著逆转SHR的左心室肥厚,降低心肌细胞横截面积和间质纤维化,其程度高于单独治疗 (p  <  0.05)。与WKY大鼠相比,RANKL,RANK和OPG的心肌表达增加。氨氯地平和阿托伐他汀均降低RANKL,RANK和OPG表达,联合使用效果最佳。根据我们的结果,RANKL/RANK/OPG系统的激活可能是导致SHR大鼠心室重构的重要因素。氨氯地平和阿托伐他汀可通过RANKL/RANK/OPG系统干预改善SHR大鼠心室重构。

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