文章摘要
郭艳如,郭萍,陈兴,等.DSG2F536C点突变基因敲入小鼠心脏表型的观察研究[J].安徽医药,2017,21(9):1590-1593.
DSG2F536C点突变基因敲入小鼠心脏表型的观察研究
Phenotype characteristics of DSG2F536C knock-in mice heart
投稿时间:2017-03-08  
DOI:
中文关键词: 致心律失常性右室心肌病  桥粒芯糖蛋白2  基因敲入小鼠  心室纤维化  转化生长因子-β1
英文关键词: 
基金项目:国家自然科学基金(81070158,81170161)
作者单位E-mail
郭艳如 南京医科大学第一附属医院心血管内科,江苏 南京 210029  
郭萍 南京医科大学第一附属医院心血管内科,江苏 南京 210029  
陈兴 南京医科大学第一附属医院心血管内科,江苏 南京 210029  
王学成 南京医科大学第一附属医院心血管内科,江苏 南京 210029  
周秀娟 南京医科大学第一附属医院心血管内科,江苏 南京 210029  
杨兵 南京医科大学第一附属医院心血管内科,江苏 南京 210029 ybheart@163.com 
陈明龙 南京医科大学第一附属医院心血管内科,江苏 南京 210029  
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中文摘要:
      目的 观察桥粒芯糖蛋白2(DSG2)点突变(DSG2F536C)基因敲入小鼠心脏结构、功能、病理学改变,并初步探讨其纤维化的发生机制。方法 构建DSG2F536C 突变基因敲入小鼠模型,分为纯合子突变组(DSG2mt/mt)、杂合子突变组(DSG2mt/wt)和野生型组(DSG2wt/wt)。分别行超声心动图检查小鼠心脏结构和功能,Masson三色染色和HE染色观察心肌组织病理特点,并用Western blot法测定心肌组织转化生长因子-β1(TGF-β1)的蛋白表达。结果 与DSG2wt/wt组小鼠相比,DSG2mt/wt组小鼠左室射血分数和缩短分数显著降低,DSG2mt/mt组小鼠则较DSG2mt/wt组进一步降低,并伴有室壁明显变薄和心腔显著扩大。DSG2mt/mt组小鼠的右心室出现心肌排列紊乱、纤维化和炎性反应,约1/3的小鼠同时累及左心室,而DSG2mt/wt组小鼠仅见心肌排列紊乱。与DSG2wt/wt组小鼠相比,DSG2mt/wt组和DSG2mt/mt组小鼠心肌组织TGF-β1蛋白表达明显升高。结论 DSG2F536C小鼠表现出心室扩大、室壁变薄、心功能下降、炎性反应和心室纤维化浸润和TGF-β1升高等表征,类似于临床致心律失常性右室心肌病(ARVC)患者的表型,提示其为致病性突变。此外,DSG2F536C基因敲入小鼠为深入研究DSG2突变导致ARVC的发病机制提供了良好的动物模型。
英文摘要:
      Objective To investigate the structural, functional and pathological characteristics of DSG2F536C mutation knock-in mice heart and the preliminary pathogenesis of cardiac fibrosis. Methods DSG2F536C mutation knock-in mice were generated and assigned to three groups, i.e. homozygous mice group (DSG2mt/mt), heterozygous mice group (DSG2mt/wt) and wild type mice group (DSG2wt/wt). Structural and functional changes of mice heart were evaluated by echocardiography. Pathological characteristics of the myocardium were assessed by Masson′s trichrome staining and HE staining. Expression level of Transforming growth factor β1 (TGF-β1) was measured by Western blot.All studies were performed in mice at ten weeks of age. Results Compared with DSG2wt/wt mice, DSG2mt/wt ones hadsignificantly decreased left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), while DSG2mt/mt mice showed further dramatically decrease in LVEF and LVFS. Meanwhile, left ventricular diameter and volume were significantly increased, but left ventricular wall thickness was significantly decreased in both DSG2mt/wt and DSG2mt/mt mice. Moreover, DSG2mt/mt mice were observed to have disordered cardiac muscle, fibrosis and inflammatory cell infiltrates of cardiac myocytes in the right ventricle, and left ventricle was affected in 1/3 of them. DSG2mt/wt mice were noted to have disordered cardiac muscle only. Compared with DSG2wt/wt mice,both DSG2mt/wt and DSG2mt/mt ones showedsignificantly increased expression of cardiac TGF-β1.Conclusions DSG2F536C knock-in mice show phenotype similar to those of ARVC patients, including enlarged ventricles, thinned ventricular wall, decreased heart function, inflammatory response, ventricular fibrotic infiltration and increased TGF-β1, which indicate that the mutation might be a pathogenic cause of ARVC. In addition, DSG2F536C knock-in mice could be a useful model for the study of the pathogenesis of ARVC.
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