Cheng Hao, Wu Jian, Li Linnan, Song Xiaoyue, Xue Junqiang, Shi Yuekai, Zou Yunzeng, Ma Jianying, Ge Junbo
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
JACC Basic Transl Sci. 2024 Apr 10;9(5):631-648. doi: 10.1016/j.jacbts.2024.01.017. eCollection 2024 May.
RNA-binding proteins play multiple roles in several biological processes. However, the roles of RBM15-an important RNA-binding protein and a significant regulator of RNA methylation-in cardiovascular diseases remain elusive. This study aimed to investigate the biological function of RBM15 and its fundamental mechanisms in myocardial infarction (MI). Methylated RNA immunoprecipitation sequencing was used to explore the N6-methyladenosine (mA) difference between MI and normal tissues. Our findings showed the elevated level of mA in MI, and its transcription profile in both MI and normal tissues. RBM15 was the main regulator and its overexpression attenuated apoptosis in cardiomyocytes and improved cardiac function in mice after MI. Then, we used one target NEDD8 activating enzyme E1 subunit and its inhibitor (MLN4924) to investigate the impact of RBM15 targets on cardiomyocytes. Finally, the enhanced mA methylation in the presence of RBM15 overexpression led to the increased expression and stability of NEDD8 activating enzyme E1 subunit. Our findings suggest that the enhanced mA level is a protective mechanism in MI, and RBM15 is significantly upregulated in MI and promotes cardiac function. This study showed that RBM15 affected MI by stabilizing its target on the cell apoptosis function, which might provide a new insight into MI therapy.
RNA结合蛋白在多个生物学过程中发挥多种作用。然而，重要的RNA结合蛋白RBM15（一种RNA甲基化的重要调节因子）在心血管疾病中的作用仍不清楚。本研究旨在探讨RBM15在心肌梗死（MI）中的生物学功能及其基本机制。采用甲基化RNA免疫沉淀测序技术探究MI组织与正常组织之间N6-甲基腺苷（m⁶A）的差异。我们的研究结果显示MI中m⁶A水平升高，以及其在MI和正常组织中的转录谱。RBM15是主要调节因子，其过表达可减轻心肌细胞凋亡，并改善MI后小鼠的心功能。然后，我们使用一种靶向NEDD8激活酶E1亚基及其抑制剂（MLN4924）来研究RBM15的靶点对心肌细胞的影响。最后，RBM15过表达时m⁶A甲基化增强导致NEDD8激活酶E1亚基的表达和稳定性增加。我们的研究结果表明，m⁶A水平升高是MI中的一种保护机制，RBM15在MI中显著上调并促进心功能。本研究表明，RBM15通过稳定其在细胞凋亡功能上的靶点来影响MI，这可能为MI治疗提供新的见解。
