运动释放Irisin改善肥胖成人内皮祖细胞及其外泌体功能活性的作用机制

The rapidly increasing prevalence of obesity has been demonstrated to lead to endothelial dysfunction, becoming a major cause of cardiovascular disease. Endothelial progenitor cells (EPCs) and their released exosomes, which richly contain microRNAs, could induce endothelial repair and regeneration. The reduction of the number and functions of both EPCs and their released exosomes is associated with the development of obesity-related cardiovascular disease. In our preliminary data, we found that the number and functions of EPCs, circulating levels of exosomes and microRNAs which are associated with endothelial function were significantly enhanced by exercise intervention along with improved endothelial function. Additionally, an association between the change in irisin and the change in EPC number was also observed after the intervention. Thus, we intend to explore by human and animal experiments that: (1) the number and functions of EPCs and their released exosomes, as well as the content and types of microRNAs in exosomes are changed in obesity; (2) exercise intervention could enhance the number and functions of both EPCs and their released exosomes, and alter the content and types of microRNAs in exosomes, along with enhanced endothelial function in obesity; (3) as an exercise-induced myokine, irisin might involve in the regulation of EPCs and their released exosomes, as well as microRNAs in exosomes in obesity. This study contributes to the understanding of the mechanisms of exercise enhancing the functional capacities of both EPCs and their released exosomes and the role of irisin in exercise-induced improvement of endothelial function in obese population.

肥胖问题日趋严重，其导致的内皮功能障碍是引起心血管病的重要原因。内皮祖细胞（EPC）及其分泌的外泌体（富含microRNA），可促进血管新生和内皮修复，其数量和功能下调可能与肥胖导致心血管病的发病机制有关。我们前期工作发现运动上调肥胖者血管内皮功能、EPC数量和功能、外泌体释放以及内皮功能相关microRNA表达，且EPC数量增加与Irisin水平升高显著正相关。由此推测运动可能释放Irisin上调EPC及其外泌体数量和功能活性，改善内皮功能。为此计划通过人体和动物实验,从整体水平、器官和细胞水平到分子水平层次递进地开展研究,阐明（1）EPC数量和功能、EPC外泌体释放及其内含的内皮功能相关microRNA在肥胖中改变；（2）运动上调EPC数量和功能、EPC外泌体释放并改变其内含microRNA表达，改善肥胖血管内皮功能；（3）Irisin与以上改变密切相关。该研究有助于了解运动改善肥胖者EPC及其外泌体功能活性的机制及Irisin在其中的作用。

肥胖症是当今全球普遍关注的公共健康话题，已发展成为威胁人类健康的主要杀手。血管内皮细胞在维持血管正常功能方面起着重要作用。肥胖导致的内皮功能障碍是与肥胖和代谢相关的心血管危险因素发生发展的始动环节和关键环节,且内皮功能受损也常常伴发并加重心血管病。故此，维持肥胖人群血管内皮正常功能与完整结构在防止血管病变中起着重要作用。本项目采用人体与动物研究相结合，从整体、器官和组织、细胞、分子等不同层面阐明生活方式干预（例如运动、饮食干预）能改善肥胖症血管功能，围绕运动及饮食干预介导的mircoRNA、运动因子或肠道菌群对血管功能的调控，探讨运动与饮食干预引起肥胖症血管功能改善的分子靶向机制。结果发现：运动与饮食干预可以显著上调肥胖人群血管内皮功能、内皮祖细胞数量和功能活性、自主神经系统功能、显著下调动脉硬化程度，从而有效改善血管功能，其中关联的生物学机制及可能关键靶点主要涉及与肥胖症血管功能关系密切的mircoRNA、Irisin或肠道菌群等的改变。通过构建肥胖大鼠模型进行验证和机制研究，发现有氧运动干预显著上调肥胖大鼠血管内皮功能、内皮祖细胞数量、肠道菌群的丰度和多样性，以及外周血外泌体中的miR-214水平，进一步证实了miR-214通过COL1A2/PI3K/Akt信号通路来调控内皮祖细胞的增殖；运动激素Irisin激活血管内皮细胞膜上的TRPV4通道并促使钙离子内流，从而引起大鼠主动脉血管内皮依赖性舒张。我们的研究将为运动改善血管功能提供新的研究靶点，为运动改善心血管疾病的机制研究提供新的研究思路。