CRLF1靶向Col1a1泛素化降解调控心肌纤维化的作用及机制研究

心脏疾病严重影响着人们生活水平的提高，心肌纤维化是多种心脏疾病发生发展过程中均伴有的病理改变，但目前对心肌纤维化的研究仍不够透彻。细胞因子受体样因子1（CRLF1）是一种细胞因子，参与包括肝纤维化在内的多种疾病的调控，但是在心肌纤维化中未见报道。我们的研究发现：在心肌梗死诱导的小鼠心肌纤维化组织和过度增殖的心肌成纤维细胞中，CRLF1表达均明显升高。沉默CRLF1可以抑制细胞活力和增殖，减少胶原合成。进一步研究发现，CRLF1是直接在成纤维细胞内起作用，其在不影响一型胶原a1亚基（Col1a1）转录水平的情况下，直接与Col1a1结合并抑制E3泛素连接酶NEDD4对Col1a1的泛素化修饰，从而打破胶原合成和降解的动态平衡，促进心肌纤维化的发生。本研究拓展了CRLF1和心肌纤维化的研究，为心肌纤维化治疗提供了新的干预靶点。

Heart diseases have a serious impact on the improvement of people's life quality. Myocardial fibrosis is a pathological change in the occurrence and development of a variety of heart diseases, but the research on myocardial fibrosis is still not thorough enough. Cytokine receptor like factor 1 (CRLF1) is a cytokine involved in the regulation of many diseases including liver fibrosis, but it has not been reported in myocardial fibrosis. Our study found that the expression of CRLF1 was significantly increased in mouse myocardial fibrosis tissues induced by myocardial infarction and over-proliferated cardiac fibroblasts. Silencing CRLF1 inhibited cell viability and proliferation, and reduced collagen synthesis. Further studies showed that CRLF1 directly acted in fibroblasts. It directly bound to Col1a1, and inhibited the ubiquitination of E3 ubiquitin ligase NEDD4 on Col1a1 without affecting the transcription level of Col1a1, thus breaking the dynamic balance of collagen synthesis and degradation, and promoting myocardial fibrosis. This study expands the research of CRLF1 and myocardial fibrosis, and provides a new intervention target for the treatment of myocardial fibrosis.