| TMEM43-S358L mutation enhances NF-κBTGFp signal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy |
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| 作者姓名： | Guoxing Zheng Changying Jiang Yulin Li Dandan Yang Youcai Ma Bing Zhang Xuan Li Pei Zhang Xiaoyu Hu Xueqiang Zhao Jie Du Xin Lin |
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| 作者单位： | Tsinghua University-Peking University Joint Center for Life Sciences;Institute for Immunology;The 7th Affiliated Hospital of Sun Yat-Sen University;Department of Molecular and Cellular Oncology;Beijing Anzhen Hospital |
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| 基金项目： | grants from National Natural Science Foundation of China(81570211 to X.Lin);China Postdoctoral Science Foundation(023221010 to G.Zheng). |
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| 摘 要： | 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 patholo.gies of ARVD patients,including structural abnormalities and cardiac fibrofatty.TMEM43 S358L mutation led to hyper-activated nuclear factor kB(NFkB)activation in heart tissues and primary cardiomy.ocyte cells.Importantly,this hyper activation of NF-κB directly drove the expression of pro-fibrotic gene,transforming growth factor beta(TGFβ),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.
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| 关 键 词： | TMEM43 ARVD NF-ΚB TGFΒ FIBROSIS KNOCK-IN mouse |
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