Sun Weihan, Fang Xinyu, Zhang Heng, Lu Yijian, Wang Peiyan, Li Jiaxin, Li Mengyang
Acta Biochim Biophys Sin (Shanghai). 2024 Aug 7;57(3):365-377. doi: 10.3724/abbs.2024103.
Aberrant gene expression in cardiomyocyte has been revealed to be the fundamental essence of pathological cardiac hypertrophy. However, the detailed mechanisms are not fully understood. The underlying regulators of gene expression involved in cardiac hypertrophy remain to be further identified. Here, we report that the RNA-binding protein RNA-binding motif protein 4 (RBM4) functions as an endogenic protector that is able to fight against cardiomyocyte hypertrophy . Under pro-hypertrophic stimulation of angiotensin II (Ang II), the protein level of RBM4 in cardiomyocyte and myocardium is elevated. Knockdown of can further aggravate cardiomyocyte hypertrophy, while over-expression of RBM4 represses cardiomyocyte hypertrophy. Mechanistically, RBM4 is localized in the nucleus and down-regulates the expression of polypyrimidine tract-binding protein 1 (PTBP1), which has been shown to aggravate cardiomyocyte hypertrophy. In addition, we suggest that the up-regulation of RBM4 in cardiomyocyte hypertrophy is caused by N6-methyladenosine (m6A). Ang II induces m6A methylation of mRNA, which further enhances the YTH domain-containing family protein 1 (YTHDF1)-mediated translation of RBM4. Thus, our results reveal a novel pathway consisting of m6A, RBM4 and PTBP1, which is involved in cardiomyocyte hypertrophy.
心肌细胞中的异常基因表达已被揭示为病理性心脏肥大的根本本质。然而，其详细机制尚未完全阐明。参与心脏肥大的基因表达的潜在调节因子仍有待进一步确定。在此，我们报告RNA结合蛋白RNA结合基序蛋白4（RBM4）作为一种内源性保护因子，能够对抗心肌细胞肥大。在血管紧张素II（Ang II）的促肥大刺激下，心肌细胞和心肌中RBM4的蛋白水平升高。敲低RBM4可进一步加重心肌细胞肥大，而RBM4的过表达则抑制心肌细胞肥大。机制上，RBM4定位于细胞核并下调多嘧啶序列结合蛋白1（PTBP1）的表达，PTBP1已被证明可加重心肌细胞肥大。此外，我们认为心肌细胞肥大中RBM4的上调是由N6-甲基腺苷（m6A）引起的。Ang II诱导RBM4 mRNA的m6A甲基化，这进一步增强了含YTH结构域家族蛋白1（YTHDF1）介导的RBM4翻译。因此，我们的结果揭示了一条由m6A、RBM4和PTBP1组成的新途径，该途径参与心肌细胞肥大。
