ExosomalmiR-143介导的心脏成纤维细胞-心肌细胞间对话引起心肌细胞凋亡的作用和机制研究

Cardiac fibroblasts (CFs) contribute to the development of heart failure by secreting biologically active ingredients. The exosome is an important organelle to allow transmission of intercellular information between cells. However, whether CFs affect cardiomyocyte apoptosis by secreting exosome miRNAs remains elusive. Our group previously found that mechanical stress promotes the paracrine of exosomal miR-143 in CFs, which triggers a significant increase in cardiomyocyte apoptosis. Therefore, we propose that the crosstalk between CFs and cardiomyocytes mediated by exosomal miR-14 might promote cardiomyocyte apoptosis. This study will employ fluorescence co-localization, and dynamic live cell imaging techniques step by step to clarify how the exosomal miR-143 is secreted from CFs, endocyted into cardiomyoctes, and govern the target gene ACE2 and PI3K/Akt-mediated signaling pathways. Animal models will be used for further verification. This project will focus on clarification of the mechanism of pressure overload-induced apoptosis from a new perspective. Completion of this project will provide new insights and target for prevention and treatment of heart failure.

心脏成纤维细胞（CFs）通过分泌生物活性成分促进心力衰竭的发展。而exosome是传递胞间信息的重要小体，但CFs分泌的exosome对心肌细胞凋亡的作用尚未明确。本课题组的预实验发现：机械牵张促进CFs分泌exosomal miR-143，exosomal miR-143引起心肌细胞凋亡显著增多。据此我们提出"exosomal miR-143介导的CFs-心肌细胞间对话引起心肌细胞凋亡"的假说。本研究拟采用荧光共定位、动态活细胞成像等技术分步骤阐明exosomal miR-143从CFs分泌、胞吞进入心肌细胞、调控细胞内靶基因ACE2和PI3K/Akt信号通路等各效应阶段的现象及机制；并通过动物模型验证exosomal miR-143介导CFs对话心肌细胞、进而促进心肌细胞凋亡的作用。本课题从exosomal miRNA的新视角研究CFs引起心肌细胞凋亡的机制，为心力衰竭防治提供新靶点。

压力超负荷诱导心脏重构进而引起心力衰竭。心脏成纤维细胞（CFs）通过分泌外泌体miRNAs促进心脏重构。但心脏成纤维细胞分泌的外泌体miRNAs对心肌细胞凋亡的作用尚未明确。我们的课题发现：机械牵张显著促进心脏成纤维细胞分泌外泌体miR-143，心脏成纤维细胞通过外泌体miR-143对话心肌细胞。本研究采用荧光共定位等技术阐明exosomal miR-143从CFs分泌、胞吞进入心肌细胞。有趣的是我们发现心脏成纤维细胞分泌的exosomal miR-143引起心肌细胞凋亡显著增多。干扰miR-143显著减少外泌体诱导的心肌细胞凋亡。在体研究同样证实干扰miR-143减少外泌体诱导的心肌细胞凋亡并改善心脏功能。我们的研究证实：心脏成纤维细胞分泌的exosomal miR-143引起心肌细胞凋亡，为心力衰竭防治提供新靶点。