M2巨噬细胞外泌体lncRNA TINCR介导TGF-β/Smad通路促进心肌纤维化和心衰的机制研究

心肌纤维化（myocardial fibrosis）是导致心力衰竭的重要因素，其进程中巨噬细胞起到关键作用，因此了解巨噬细胞影响心肌纤维化的病理机制是心衰防治研究的重点和难点。申请人前期研究发现TGFβ1/Smad通路可心脏成纤维细胞（cardiac fibroblast, CFBs）转分化，同时lncRNA可增强心肌纤维化进展。通过对巨噬细胞和心肌纤维化的芯片分析，结合前期预实验佐证提出假说：心肌组织中驻留的M2巨噬细胞一方面可分泌促纤维因子TGFβ1，另一方面又可分泌外泌体lncRNA TINCR结合Smad3，增强 Smads复合物的转录活性，增强TGFβ1诱导的CFBs转分化，促进心肌纤维化和心衰进程。通过细胞实验，动物模型和临床样本验证探讨巨噬细胞外泌体介导的lncRNA传递对CFBs细胞通讯潜能和表型转分化的影响，进一步阐明心肌纤维化的发病机制，为预防和治疗心衰提供新的思路。

Myocardial fibrosis is an important factor leading to heart failure. Macrophages play a key role in the process. Therefore, it is the key and difficult point to understand the pathological mechanism of macrophages affecting myocardial fibrosis. The applicant's previous study found that TGFβ1/Smad pathway can transdifferentiate cardiac fibroblasts (CFBs), while lncrna can enhance the progress of myocardial fibrosis. Based on the microarray analysis of macrophages and myocardial fibrosis, the hypothesis was put forward in combination with pre experiment：On the one hand, M2 macrophages resident in cardiac tissue can secrete TGFβ1, on the other hand, they can secrete lncrna tincr combined with Smad3, enhance the transcription activity of Smads complex, enhance CFBs transdifferentiation induced by TGFβ1, and promote the process of myocardial fibrosis and heart failure. Through cell experiment, animal model and clinical sample verification, this paper discusses the influence of macrophage exosomes mediated lncrna transfer on the communication potential and phenotype transdifferentiation of CFBs cells, further clarifies the pathogenesis of myocardial fibrosis, and provides new ideas for the prevention and treatment of heart failure.