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-β_1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-β_1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。 Objective To observe the cardiac structure, function and pathology of DSG2 point mutation (DSG2 ~ (F536C)) knockout mice and to investigate the possible mechanism of their fibrosis. Methods DSG2 ~ (F536C) gene knock - in mouse model was established and divided into four groups: DSG2 ~ (mt / mt), DSG2 ~ (mt / wt) ~ (wt / wt)). The structure and function of the heart of the mice were examined by echocardiography. Masson’s trichrome staining and HE staining were used to observe the pathological features of the myocardium. The protein expression of transforming growth factor-β1 (TGF-β1) in myocardium was detected by Western blot. Results Compared with DSG2 ~ (wt / wt) group, the left ventricular ejection fraction and shortening fraction in DSG2 ~ (mt / wt) group were significantly decreased, while those in DSG2 ~ (mt / (mt / wt) group further reduced, accompanied by significant thinning of the wall and heart chamber was significantly expanded. About 1% of mice in DSG2 ~ (mt / mt) group had right ventricular dysfunction, fibrosis and inflammatory reaction in right ventricle, and left ventricular in left ventricular in DSG2 ~ (mt / mt) Disorderly arranged. Compared with DSG2 ~ (wt / wt) group, the expression of TGF-β1 in myocardium of DSG2 ~ (mt / wt) group and DSG2 ~ (mt / mt) group was significantly increased. Conclusions DSG2 ~ (F536C) mice showed signs of ventricular enlargement, thinning of the wall, decreased cardiac function, inflammatory response and infiltration of ventricular fibrosis and elevated TGF-β_1, similar to those of clinically induced arrhythmogenic right ventricular cardiomyopathy ARVC) patients, suggesting that it is a pathogenic mutation. In addition, DSG2 ~ (F536C) knock-in mice provide a good animal model for further study on the pathogenesis of ARVC induced by DSG2 mutation.