肥大心肌细胞来源胞外体在TLR7介导的心肌炎症反应调节中的作用及机制

心肌肥大与多种心血管疾病相关，严重危害人类健康。胞外体介导的炎症通路在心肌肥大发生发展中作用关键，但机制不详。我们研究显示，血管紧张素II诱导的肥大心肌细胞来源胞外体中miR-29a表达明显增加，但其具体的microRNAs（miRNAs）表达特征尚不清楚。在预实验中，我们发现：肥大心肌细胞来源胞外体能活化巨噬细胞TLR7信号通路。资料表明，TLR7是心肌炎症反应的重要调控因子。因此，我们推测：肥大心肌细胞来源胞外体携带的miRNAs表达发生变化，并经TLR7影响心肌炎症反应。本项目拟应用透射电子显微镜、基因芯片等技术研究肥大心肌细胞来源胞外体大小、形态、分泌量、miRNAs表达等特征，进一步采用激光共聚焦显微镜、流式细胞仪、免疫共沉淀等技术，从整体-器官-细胞层次观察肥大心肌细胞来源胞外体对心肌炎症反应的影响，并探讨其分子机制。此研究将为心肌肥大和心力衰竭的防治提供新思路和新靶点。

Cardiac hypertrophy was found to be associated with several cardiovascular diseases, which seriously threaten people’s health. The exosome-mediated inflammatory pathway was proposed to play an important role in the occurrence and development of cardiac hypertrophy, but the molecular mechanisms remain poorly understood. Our results showed that the expression of miR-29a was significantly enhanced in exosomes derived from hypertrophic cardiac myocytes induced with angiotensin II. However, the miRNA expression profile in such exosomes is currently unknown. In a preliminary experiment we further found that exosomes derived from hypertrophic cardiac myocytes were capable of activating Toll-like receptors 7 (TLR7) in macrophages. Recently, emerging data have indicated that TLR7 was an important regulator of cardiac inflammation. Therefore, we suppose that cardiac hypertrophy leads to changes of exosomes derived from hypertrophic cardiac myocytes in miRNA content, which contribute to inflammatory response in a TLR7 mediated manner. The aim of this study is to detect the relevant properties of exosomes include size, morphology, production and miRNA content using transmission electron microscope and miRNA microarray. Also, the effect of exosomes on cardiac inflammation and its possible mechanism will be investigated at whole body, organ and cellular levels using laser confocal microscope, flow cytometry and co-Immunoprecipitation. This work has the potential to bring new ideas and targets for the successful prevention and treatment of cardiac hypertrophy and heart failure.