Brodehl Andreas, Belke Darrell D, Garnett Lauren, Martens Kristina, Abdelfatah Nelly, Rodriguez Marcela, Diao Catherine, Chen Yong-Xiang, Gordon Paul M K, Nygren Anders, Gerull Brenda
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada.
PLoS One. 2017 Mar 24;12(3):e0174019. doi: 10.1371/journal.pone.0174019. eCollection 2017.
Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, mainly as a result of mutations in cardiac desmosomal genes. Desmosomes are cell-cell junctions mediating adhesion of cardiomyocytes; however, the molecular and cellular mechanisms underlying the disease remain widely unknown. Desmocollin-2 is a desmosomal cadherin serving as an anchor molecule required to reconstitute homeostatic intercellular adhesion with desmoglein-2. Cardiac specific lack of desmoglein-2 leads to severe cardiomyopathy, whereas overexpression does not. In contrast, the corresponding data for desmocollin-2 are incomplete, in particular from the view of protein overexpression. Therefore, we developed a mouse model overexpressing desmocollin-2 to determine its potential contribution to cardiomyopathy and intercellular adhesion pathology.
We generated transgenic mice overexpressing DSC2 in cardiac myocytes. Transgenic mice developed a severe cardiac dysfunction over 5 to 13 weeks as indicated by 2D-echocardiography measurements. Corresponding histology and immunohistochemistry demonstrated fibrosis, necrosis and calcification which were mainly localized in patches near the epi- and endocardium of both ventricles. Expressions of endogenous desmosomal proteins were markedly reduced in fibrotic areas but appear to be unchanged in non-fibrotic areas. Furthermore, gene expression data indicate an early up-regulation of inflammatory and fibrotic remodeling pathways between 2 to 3.5 weeks of age.
Cardiac specific overexpression of desmocollin-2 induces necrosis, acute inflammation and patchy cardiac fibrotic remodeling leading to fulminant biventricular cardiomyopathy.
致心律失常性心肌病是一种遗传性心肌疾病，主要由于心脏桥粒基因的突变导致室性心律失常和心力衰竭。桥粒是介导心肌细胞黏附的细胞间连接；然而，该疾病潜在的分子和细胞机制仍不清楚。桥粒芯蛋白-2是一种桥粒钙黏蛋白，作为与桥粒芯糖蛋白-2重建稳态细胞间黏附所需的锚定分子。心脏特异性缺乏桥粒芯糖蛋白-2会导致严重的心肌病，而过度表达则不会。相比之下，关于桥粒芯蛋白-2的相应数据并不完整，特别是从蛋白质过度表达的角度来看。因此，我们构建了一个过度表达桥粒芯蛋白-2的小鼠模型，以确定其对心肌病和细胞间黏附病理的潜在影响。
我们构建了在心肌细胞中过度表达DSC2的转基因小鼠。二维超声心动图测量显示，转基因小鼠在5至13周内出现严重的心功能障碍。相应的组织学和免疫组化显示纤维化、坏死和钙化，主要位于两个心室的心内膜和心肌膜附近的斑块中。纤维化区域内源性桥粒蛋白的表达明显降低，但在非纤维化区域似乎没有变化。此外，基因表达数据表明，在2至3.5周龄之间，炎症和纤维化重塑途径早期上调。
心脏特异性过度表达桥粒芯蛋白-2会诱导坏死、急性炎症和散在性心脏纤维化重塑，导致暴发性双心室心肌病。
