Early inflammation precedes cardiac fibrosis and heart failure in desmoglein 2 murine model of arrhythmogenic cardiomyopathy.
Early inflammation precedes cardiac fibrosis and heart failure in desmoglein 2 murine model of arrhythmogenic cardiomyopathy.
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DOI：
10.1007/s00441-021-03488-7
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发表时间：
2021-10
影响因子：
3.6
通讯作者：
Tinker A
中科院分区：
文献类型：
--
作者：
Ng KE;Delaney PJ;Thenet D;Murtough S;Webb CM;Zaman N;Tsisanova E;Mastroianni G;Walker SLM;Westaby JD;Pennington DJ;Pink R;Kelsell DP;Tinker A
桥粒芯糖蛋白2致心肌病小鼠模型的研究揭示了心脏炎症是导致纤维化的关键早期事件。致心律失常性心肌病（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桥粒芯糖蛋白2（Dsg 2）的缺失如何导致AC的发展。细胞凋亡是一种早期细胞表型，RNA测序分析显示，在出生后第14天（2周），Dsg 2-null（Dsg 2 −/−）心脏中的炎症相关途径早期激活，而成年小鼠（10周）的纤维化心脏中不存在。这包括iRhom 2/ADAM 17及其相关促炎细胞因子和受体（如TNFα、IL 6 R和IL-6）的上调。此外，与特定巨噬细胞群体相关的基因也被上调。这表明心肌细胞应激触发早期免疫反应以清除凋亡细胞，从而允许纤维化心脏中的组织重塑。我们在疾病早期阶段的分析表明，心脏炎症是一种重要的反应，可能是AC疾病进展的机制之一。在线版本包含补充材料，可通过10.1007/s 00441 -021-03488-7获得。
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. Apoptosis was an early cellular phenotype, and RNA sequencing analysis revealed early activation of inflammatory-associated pathways in Dsg2-null (Dsg2−/−) hearts at postnatal day 14 (2 weeks) that were absent in the fibrotic heart of adult mice (10 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 also 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 the early disease stage suggests cardiac inflammation is an important response and may be one of the mechanisms responsible for AC disease progression. The online version contains supplementary material available at 10.1007/s00441-021-03488-7.
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影响因子：
39.3
作者：
Chatterjee, Diptendu;Fatah, Meena;Hamilton, Robert M.
通讯作者：
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影响因子：
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作者：
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Chávez-Galán L;Olleros ML;Vesin D;Garcia I
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Garcia I
DOI：
10.1016/b978-0-12-394311-8.00005-4
发表时间：
2013
影响因子：
--
作者：
Kowalczyk, Andrew P.;Green, Kathleen J.
通讯作者：
Green, Kathleen J.