Early cardiac inflammation as a driver of murine model of Arrhythmogenic Cardiomyopathy
Early cardiac inflammation as a driver of murine model of Arrhythmogenic Cardiomyopathy
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DOI：
10.1101/2020.06.24.169664
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发表时间：
2020-06
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通讯作者：
K. Ng;P. Delaney;D. Thenet;S. Murtough;C. M. Webb;E. Tsisanova;Sophie L.M. Walker;J. Westaby;Daniel J. Pennington;Ryan C. Pink;David P. Kelsell;Andrew Tinker
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作者：
K. Ng;P. Delaney;D. Thenet;S. Murtough;C. M. Webb;E. Tsisanova;Sophie L.M. Walker;J. Westaby;Daniel J. Pennington;Ryan C. Pink;David P. Kelsell;Andrew Tinker
对致心律失常性心肌病小鼠模型的研究表明，心脏炎症是导致纤维化的关键早期事件。心律失常性心肌病（AC）是一种遗传性心肌疾病，由于心脏桥粒异常导致室性心律失常和心力衰竭。我们研究了年轻小鼠心脏中desmoglin 2 （Dsg2）的缺失如何导致AC的发展。心肌细胞凋亡是一种早期细胞表型，RNA-Seq分析显示，在出生后第14天（2周），Dsg2缺失（Dsg2−/−）的心脏中，炎症相关通路的早期激活在成年小鼠（10周）的纤维化心脏中是不存在的。这包括iRhom2/ADAM17及其相关的促炎细胞因子和受体如TNFα、IL6R和IL-6的上调。此外，与特定巨噬细胞群体相关的基因被上调。这表明心肌细胞应激触发了清除凋亡细胞的早期免疫反应，允许纤维化心脏稍后进行组织重塑。我们在不同疾病阶段的分析表明，与黏着蛋白2缺失相关的炎症是疾病进展的主要机制。
The study of a desmoglein 2 murine model of arrhythmogenic cardiomyopathy revealed cardiac inflammation as a key early event leading to fibrosis. Arrhythmogenic Cardiomyopathy (AC) is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure due to abnormalities in the cardiac desmosome. We examined how loss of desmoglein 2 (Dsg2) in the young murine heart leads to development of AC. Cardiomyocyte apoptosis was an early cellular phenotype and RNA-Seq analysis revealed early activation of inflammatory-associated pathways in Dsg2 null (Dsg2−/−) hearts at postnatal day 14 (Two weeks) that were absent in the fibrotic heart of adult mice (Ten weeks). This included upregulation of iRhom2/ADAM17 and its associated pro-inflammatory cytokines and receptors such as TNFα, IL6R and IL-6. Furthermore, genes linked to specific macrophage populations were upregulated. This suggests cardiomyocyte stress triggers an early immune response to clear apoptotic cells allowing tissue remodelling later on in the fibrotic heart. Our analysis at different disease stages implicate inflammation related to loss of desmoglein 2 as a major mechanism for disease progression.