Chen Chuansheng, Wang Guanghua, Zou Qicheng, Xiong Ke, Chen Zhiwen, Shao Beihua, Liu Yi, Xie Duanyang, Ji Yong
Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, 211166, China.
State Key Laboratory of Cardiovascular Diseases, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
Sci China Life Sci. 2025 Mar;68(3):706-721. doi: 10.1007/s11427-024-2674-2. Epub 2024 Oct 18.
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. N-methyladenosine (mA), 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 mA regulatory proteins in the onset of AF remains unclear. Here, we demonstrate that the mA 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 mA-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 mA-independent manner, thereby facilitating the onset of AF. Our study suggests that YTHDF2 may be a potential intervention target for AF.
心房颤动（AF）是最常见的心律失常，它与心房心肌细胞中离子通道的异常表达和功能密切相关。N-甲基腺苷（mA）是真核生物mRNA中广泛存在的一种化学修饰，已知其在心脏病发病机制中发挥重要的调节作用。然而，mA调节蛋白在AF发病中的意义仍不清楚。在此，我们证明mA识别蛋白YTHDF2通过调节Cav1.2的表达来调控心房电重构和AF的发生。首先，在患有AF的大鼠心房心肌细胞中，YTHDF2的表达选择性上调。其次，YTHDF2基因敲除降低了小鼠对AF的易感性。第三，YTHDF2基因敲除以不依赖于mA的方式增加了Cav1.2蛋白水平，最终延长了心房心肌不应期，这是AF发生的关键电生理基础。第四，YTHDF2的N端结构域被确定为对Cacna1c mRNA翻译调控至关重要。总体而言，我们的研究结果揭示YTHDF2可以不依赖于mA的方式改变Cav1.2蛋白表达，从而促进AF的发生。我们的研究表明YTHDF2可能是AF的一个潜在干预靶点。
