2. Academic Validation
  3. m6A reader YTHDF2 governs the onset of atrial fibrillation by modulating Cacna1c translation

m6A reader YTHDF2 governs the onset of atrial fibrillation by modulating Cacna1c translation

  • Sci China Life Sci. 2024 Oct 18. doi: 10.1007/s11427-024-2674-2.
Chuansheng Chen # 1,  Guanghua Wang # 2 3 4,  Qicheng Zou # 2 4,  Ke Xiong 2 4,  Zhiwen Chen 2 3 4,  Beihua Shao 2 3 4,  Yi Liu 2 4 5,  Duanyang Xie 6 7 8 9,  Yong Ji 10
Affiliations

Affiliations

  • 1 Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, 211166, China.
  • 2 State Key Laboratory of Cardiovascular Diseases, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
  • 3 Department of Pathology and Pathophysiology, School of Medicine, Tongji University, Shanghai, 200092, China.
  • 4 Department of Cardiology, School of Medicine, Tongji University, Shanghai, 200120, China.
  • 5 Shanghai Arrhythmia Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
  • 6 State Key Laboratory of Cardiovascular Diseases, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China. xieduanyang@tongji.edu.cn.
  • 7 Department of Pathology and Pathophysiology, School of Medicine, Tongji University, Shanghai, 200092, China. xieduanyang@tongji.edu.cn.
  • 8 Department of Cardiology, School of Medicine, Tongji University, Shanghai, 200120, China. xieduanyang@tongji.edu.cn.
  • 9 Shanghai Arrhythmia Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China. xieduanyang@tongji.edu.cn.
  • 10 Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, 211166, China. yongji@njmu.edu.cn.
  • # Contributed equally.
PMID: 39432207 DOI: 10.1007/s11427-024-2674-2
Abstract

Atrial fibrillation (AF) is the most common arrhythmia, which is tightly associated with the abnormal expression and function of ion channels in the atrial cardiomyocytes. N6-methyladenosine (m6A), a widespread chemical modification in eukaryotic mRNA, is known to play a significant regulatory role in the pathogenesis of heart disease. However, the significance of m6A regulatory proteins in the onset of AF remains unclear. Here, we demonstrate that the m6A reader protein YTHDF2 regulates atrial electrical remodeling and AF onset by modulating the Cav1.2 expression. Firstly, YTHDF2 expression was selectively upregulated in rat atrial cardiomyocytes with AF. Secondly, YTHDF2 knockout reduced AF susceptibility in mice. Thirdly, the knockout of YTHDF2 increased Cav1.2 protein levels in an m6A-in-dependent manner, ultimately prolonging the atrial myocardial refractory period, a critical electrophysiological substrate for the onset of AF. Fourthly, the N-terminal domain of YTHDF2 was identified as critical for Cacna1c mRNA translation regulation. Overall, our findings unveil that YTHDF2 can alter Cav1.2 protein expression in an m6A-independent manner, thereby facilitating the onset of AF. Our study suggests that YTHDF2 may be a potential intervention target for AF.

Keywords

Cacna1c translation; YTHDF2; action potential duration; atrial fibrillation; effective refractory period.

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