Abstract：
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 in vitro. Under pro-hypertrophic stimulation of angiotensin II (Ang II), the protein level of RBM4 in cardiomyocyte and myocardium is elevated. Knockdown of RBM4 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 RBM4 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.
摘要：
心肌细胞中基因的异常表达已被揭示为病理性心肌肥大的基本本质。然而,详细的机制还没有完全理解。与心脏肥大有关的基因表达的潜在调节因子仍有待进一步鉴定。这里,我们报道了RNA结合蛋白RNA结合基序蛋白4(RBM4)作为内源性保护剂,能够在体外对抗心肌细胞肥大.在血管紧张素II（AngII）的促肥大刺激下，心肌细胞和心肌中RBM4的蛋白质水平升高。敲除RBM4可进一步加重心肌细胞肥大，而RBM4的过表达抑制心肌细胞肥大。机械上,RBM4定位于细胞核中，下调聚嘧啶束结合蛋白1（PTBP1）的表达，已被证明会加重心肌细胞肥大。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。AngII诱导RBM4mRNA的m6A甲基化，进一步增强含YTH域的家族蛋白1（YTHDF1）介导的RBM4翻译。因此，我们的研究结果揭示了一种由M6A组成的新通路，RBM4和PTBP1参与心肌细胞肥大。
