Genetic Activation and Suppression of the Canonical WNT Pathway in Cardiac Myocyte-Specific Dsp Deficient Mouse Model of Arrhythmogenic Cardiomyopathy

The cWNT pathway has been implicated in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), including in cardiac dysfunction, apoptosis, and fibro-adipogenesis, the latter being the histological hallmark of ACM. The study was designed to determine effects of genetic activation or suppression of cWNT in a mouse model of arrhythmogenic cardiomyopathy. The data show that activation of the cWNT in ACM deleterious whereas it suppression is benefiial. Overall design: The cWNT signaling pawathway was activated or suppressed post-nataly (P14) using tamoxifen-inducible cre and floxed beta catenin gene while concomittantly deleting the Dsp deficiency, all specificially in cardiac myocytes. The experimental groups include wild type (WT), Myh6-MerCreMer, , Myh6-MCM:DspF/F, Myh6-MCM:Ctnnb1GoF (Gain of function) , Myh6-MCM:Ctnnb1LoF (Loss of function), Myh6-MCM:DspF/F:Ctnnb1LoF , and Myh6-MCM:DspF/F:Ctnnb1GoF/F mice. Phenotypic characterization and myocyte RNA sequencing were performed at 4 weeks of age.

经典Wnt（cWNT）通路已被证实与致心律失常性心肌病（arrhythmogenic cardiomyopathy, ACM）的发病机制密切相关，涉及心脏功能障碍、细胞凋亡以及脂肪纤维样变，后者即为ACM的组织病理学标志性特征。本研究旨在探究cWNT通路的遗传激活与抑制在致心律失常性心肌病小鼠模型中的作用效果。实验数据显示，在ACM模型中激活cWNT通路会产生有害作用，而抑制该通路则可发挥有益效果。总体实验设计：研究于小鼠出生后第14天（P14），利用他莫昔芬诱导型Cre重组酶与floxed β连环蛋白基因，在心肌细胞中特异性激活或抑制cWNT通路，同时构建DSP基因缺陷模型。实验分组包括：野生型（WT）小鼠、Myh6-MerCreMer小鼠、Myh6-MCM:DspF/F小鼠、Myh6-MCM:Ctnnb1GoF（功能获得型）小鼠、Myh6-MCM:Ctnnb1LoF（功能丧失型）小鼠、Myh6-MCM:DspF/F:Ctnnb1LoF小鼠，以及Myh6-MCM:DspF/F:Ctnnb1GoF/F小鼠。所有小鼠于4周龄时开展表型鉴定及心肌细胞RNA测序。