期刊
PROTEIN & CELL
卷 10, 期 2, 页码 104-119出版社
SPRINGEROPEN
DOI: 10.1007/s13238-018-0563-2
关键词
TMEM43; ARVD; NF-kappa B; TGF beta; fibrosis; knock-in mouse
类别
资金
- Animal Facility of Tsinghua University
- Animal Facility of the University of Texas, MD Anderson Cancer Center
- National Natural Science Foundation of China [81570211]
- China Postdoctoral Science Foundation [023221010]
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic cardiac muscle disease that accounts for approximately 30% sudden cardiac death in young adults. The Ser358Leu mutation of transmembrane protein 43 (TMEM43) was commonly identified in the patients of highly lethal and fully penetrant ARVD subtype, ARVD5. Here, we generated TMEM43 S358L mouse to explore the underlying mechanism. This mouse strain showed the classic pathologies of ARVD patients, including structural abnormalities and cardiac fibrofatty. TMEM43 S358L mutation led to hyper-activated nuclear factor kappa B (NF-kappa B) activation in heart tissues and primary cardiomyocyte cells. Importantly, this hyper activation of NF-kappa B directly drove the expression of pro-fibrotic gene, transforming growth factor beta (TGF beta 1), and enhanced downstream signal, indicating that TMEM43 S358L mutation up-regulates NF-kappa B-TGF beta signal cascade during ARVD cardiac fibrosis. Our study partially reveals the regulatory mechanism of ARVD development.
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