TRANSGENIC MICE OVEREXPRESSING DSC2 DEVELOP BIVENTRICULAR CARDIOMYOPATHY ASSOCIATED WITH FIBROSIS AND NECROSIS

Abstract

Arrhythmogenic cardiomyopathy (AC) is an inherited heart disease associated with arrhythmias and right or biventricular dilation often leading to sudden cardiac death or heart failure. AC is mainly caused by mutations in five genes encoding cardiac desmosomal proteins (JUP, DSP, PKP2, DSG2 and DSC2). The cardiac desmosomes are cell-cell junctions coupling the cardiomyocytes. Desmocollin-2 (DSC2) and desmoglein-2 (DSG2) are members of the cadherin family and mediate the Ca2+-dependent cardiomyocyte adhesion. Plakophilin-2 (PKP2), plakoglobin (JUP) and desmoplakin (DSP) are linker proteins connecting the cytoplasmic domains of these cadherins to the intermediate filament system. However, the molecular and cellular pathomechanisms induced by mutations in these genes are widely unknown limiting the efficient development of therapeutic therapies. So far, no Dsc2 mouse model mimicking an AC is described. The aim of this project was therefore to establish and characterize an adequate mouse model to understand the underlying pathomechanisms in vivo and ex vivo. We developed and characterized a transgenic mouse model with a cardiac-specific overexpression of DSC2. Echocardiography was used to characterize the heart function and (immuno)histology was used to characterize the structural defects the transgenic mice. Western-blot analysis and qRT-PCR was used to characterize the molecular expression changes of the desmosomal genes. Transgenic mice with a cardiac specific overexpression of DSC2 developed a severe cardiomyopathy shortly after birth with significantly reduced fractional shortening and ejection fractions. Time-dependent functional analysis revealed that the phenotype is deteriorating leading to heart failure and cardiac death after 12 weeks. The myocardial tissue of the septum as well as of both ventricular walls was significantly replaced by fibrosis and was associated with calcification and necrosis in these areas. The established cardiac specific overexpressing DSC2 mice are viable but develop a progressive biventricular cardiomyopathy mimicking the clinical phenotype of patients with arrhythmogenic cardiomyopathy. In the future this novel mouse model could contribute to further understanding of the molecular and cellular pathomechanisms leading to AC.