环形RNA circ_0036167通过FUS/CPEB4轴发挥抑制心肌纤维化作用的机制研究

我们证实小鼠环形RNA circRNA_000203结合微小RNAs发挥促心肌纤维化作用（Cardiovasc Res. 2019），近期发现与之同源的人 circ_0036167在心肌纤维化时亦上调，定位于胞核，发挥抑制心肌纤维化作用。circ_0036167与融合肉瘤(FUS)RNA结合蛋白作用，解除FUS稳定胞质多糖基化元件结合蛋白4（CPEB4）mRNA作用而使CPEB4下调；CPEB4下调后TNF-α翻译受阻使Smad2/3失活。推测circ_0036167特异结合FUS，减弱FUS稳定CPEB4 mRNA作用，并降低CPEB4-TNF-α/Smad2/3活化和纤维化相关基因表达。拟建立心肌特异表达circ_0036167小鼠，从整体-细胞-分子水平阐明FUS/CPEB4轴介导circ_0036167抑制心肌纤维化的机制，为以circRNA为靶点的心肌纤维化治疗研究提供科学依据。

We have reported that circular RNA circRNA_000203 plays a role in cardiac remodeling via binding the related microRNAs in the cytoplasm of mouse cardiomyocytes (Cardiovasc Res, 2019). Recently, we found that the expression of homologous human circ_0036167 was increased in the myocardium of patients with heart failure and in human atrial fibroblasts exposed to Ang-II treatment. Circ_0036167 is mainly distributed in the nucleus of human atrial fibroblasts, which could inhibit the expression of fibrosis-related genes. Circ_0036167 could interact with fusion sarcoma (FUS) RNA binding protein, abolishing the effect of FUS on mRNA stability of cytoplasmic polysaccharide element binding protein 4 (CPEB4) gene, resulting in the decrease of CPEB4. Moreover, down-regulation of CPEB4 inhibited TNF-α translation, Smad2/3 activation and the expression of fibrosis-related genes in cardiac fibroblasts. We speculate that circ_0036167 can specifically bind FUS, and weaken the stabilizing effect of FUS on CPEB4 mRNA, contributing to reducing the activation of CPEB4-TNF-α/Smad2/3 signal and the expressions of CPEB4 and fibrosis-related genes. To elucidate the molecular mechanism of FUS/CPEB4 axis mediates the inhibitory effect of circ_0036167 on myocardial fibrosis on levels of body, cell and molecule, a mouse model with myocardial specific overexpression of circ_0036167 will be established and used in this project, so as to provide scientific basis and data for the treatment of myocardial fibrosis with circRNAs as the intervention targets.