Changying Jiang
Yulin Li
Dandan Yang
Youcai Ma
Bing Zhang
Xuan Li
Pei Zhang
Xiaoyu Hu
Xueqiang Zhao
Jie Du
Xin Lin
1 Tsinghua University-Peking University Joint Center for Life Sciences, Beijing 100084, China;
2 Institute for Immunology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China;
3 The 7th Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong 510275, China;
4 Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA;
5 Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing 100029, China
Funds: This work was supported by grants from National Natural Science Foundation of China (81570211 to X. Lin), and China Postdoctoral Science Foundation (023221010 to G. Zheng).
Received Date: 2017-11-22
Rev Recd Date:2018-06-12
Abstract
Abstract
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 κB (NF-κB) activation in heart tissues and primary cardiomyocyte cells. Importantly, this hyper activation of NF-κB directly drove the expression of pro-fibrotic gene, transforming growth factor beta (TGFβ1), and enhanced downstream signal, indicating that TMEM43 S358L mutation up-regulates NF-κB-TGFβ signal cascade during ARVD cardiac fibrosis. Our study partially reveals the regulatory mechanism of ARVD development.Keywords: TMEM43,
ARVD,
NF-κB,
TGFβ,
fibrosis,
knock-in mouse
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