外泌体miRNAs介导细胞间应答网络调控心房代谢重构在心房颤动中的作用与机制

房颤是威胁健康的重大疾病。新近我们和国内外同行均发现心房代谢重构能够引起电和结构重构促进房颤发生，但确切机制不清。外泌体miRNA通过细胞间通讯构建调控网络，在重大心血管疾病中发挥重要作用。我们前期发现：高频电刺激使心房肌、成纤维和心外膜脂肪细胞分泌的外泌体miRNA表达谱发生显著变化，经生物信息学分析并与房颤患者血浆差异表达的外泌体miRNA比对，筛选出介导细胞能量代谢调控的6个外泌体miRNA（miR-22等）；体外和在体研究证实，心房肌细胞和心外膜脂肪细胞来源的外泌体miR-22引起成纤维细胞代谢障碍，导致纤维化，促进房颤发生。我们假设：一组外泌体miRNA介导细胞间应答网络通过调控代谢重构，引起心房电和结构重构，促进房颤发生并持续。我们将运用模式动物、生物信息学和功能学等方法，阐明外泌体miRNA调控心房代谢重构的作用和机制，揭示代谢重构在房颤发生中的确切作用，寻找防治新靶点。

Atrial fibrillation (AF) is a major disease threatening human health. Recently, we and peers from domestic and foreign laboratories have found that atrial metabolic remodeling could cause atrial electrical and structural remodeling and promote AF, but its exact molecular mechanism is still unclear. Exosomal miRNAs play important roles in major cardiovascular diseases by constructing a regulatory network through intercellular communications. We previously found that: miRNA profile of exosomes originated from atrial myocyte, fibroblast and epicardial adipocyte after high frequency electrical stimulation was significantly changed. Six exosomal miRNA (miR-22 etc.) associated with inter-cellular energy metabolism was screened through bioinformatical analysis and comparison with plasma exosomal miRNA profile of AF patients; Both in vivo and in vitro studies demonstrated that exosomal miR-22 from atrial myocyte and epicardial adipocyte aggravated metabolic dysfunction of cardiac fibroblast and thereby induced cardiac fibrosis and eventually promoted the occurrence of AF. Based on these findings, we hypothesized that a group of exosomal miRNAs-mediated intercellular response network promotes atrial electrical and structural remodeling by regulating metabolic remodeling, resulting in the occurrence and persistence of AF. We will use the comprehensive techniques of bioinformatical, functional and molecular biology as well as transgenic animal models to elucidate the role and mechanism of a group of exosomal miRNAs in regulating atrial metabolic remodeling. Our study will clarify the exact role of metabolic remodeling in the progression of AF, and provide novel targets for prevention and treatment.