期刊
CELL AND TISSUE RESEARCH
卷 386, 期 1, 页码 79-98出版社
SPRINGER
DOI: 10.1007/s00441-021-03488-7
关键词
Desmoglein 2 (Dsg2); Arrhythmogenic cardiomyopathy (AC); Desmosome; Cardiac inflammation and macrophages
类别
资金
- British Heart Foundation [RG/13/19/30568]
The study revealed that cardiac inflammation is a key early event leading to fibrosis in arrhythmogenic cardiomyopathy. Loss of desmoglein 2 in the young murine heart resulted in apoptosis and upregulation of inflammatory-associated pathways, suggesting an early immune response triggers tissue remodelling in the fibrotic heart. This analysis indicates that cardiac inflammation plays an important role in AC disease progression.
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 TNF alpha, 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.
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