心肌外泌体通过巨噬细胞介导心脏修复的机制研究

缺血性心脏病是威胁我国人民健康的头号杀手，缺血损伤后修复是影响预后的关键。目前认为，巨噬细胞是缺血心脏损伤修复的主要细胞类型：早期介导炎性反应，后期介导抗炎反应，促进坏死细胞和组织碎片清除、以及血管再生。外泌体是由正常或病理状态细胞分泌的双层脂质结构的小囊泡，在心脏应激状态下的旁分泌机制中起到重要的网络交通作用。前期研究结果表明，急性心肌梗死（AMI）后，心肌释放大量外泌体，携带miRNA（AMI-exo-miRNA）并将其有效转运至骨髓来源的单个核细胞，促进缺血心脏修复，但其对巨噬细胞的功能调节尚未知。因此，本课题拟进一步探讨AMI-exo-miRNA在缺血损伤部位通过巨噬细胞发挥旁分泌作用参与心脏缺血损伤后修复的分子机制。证实心肌细胞除了介导心肌收缩、维持泵功能之外，还通过旁分泌作用介导缺血损伤修复，为缺血性心脏病提供新的潜在治疗靶点。

Ischemic heart disease is the number one killer in China, and post-ischemic repair is crucial for the prognosis. Increasing evidence now suggests that macrophages play a major role in the cardiac ischemic repair; they mediate inflammatory response in the early stage and anti-inflammatory response in the later stage, eliminate dead and dying cells and tissue debris, and promote vascular regeneration. Exosomes are bilayer lipid vesicles secreted by normal or pathological cells to play an important role in mediating inter-cellular communications via paracrine mechanisms. In preliminary studies we found that after acute myocardial infarction (AMI), a large quantity of exosomes are released in the ischemic myocardium, which carry and transport cardiac miRNA (AMI-exo-miRNA) into bone marrow-derived mononuclear cells (BM MNCs), enhancing cardiac repair. Although monocytes/macrophages are a major component of the BM MNCs, their roles in AMI-exo-miRNA mediated cardiac repair remain unexplored, and their specific functions that are controlled by AMI-exo-miRNAs are unknown. This proposal is aimed to determine how AMI-exo-miRNAs regulate the function of cardiac macrophages, the underlying molecular mechanisms, and the significance of regulation in ischemic cardiac repair. Successful completion of this research will establish that cardiomyocytes, beyond their contractile and pump function, can also promote ischemic repair via paracrine mechanisms and may identify new therapeutic target for treatment of ischemic heart disease.