心包液外泌体miR-548ay-3p靶向抑制心外膜脂肪细胞PPAR-γ调控房颤心房结构重构的作用及机制研究

房颤显著增加栓塞及心衰风险，房颤患者出现心外膜脂肪（EAT）内脂肪细胞肥大、间质纤维化和脂肪因子分泌紊乱。EAT结构改变及分泌紊乱是EAT诱发或加重房颤心房结构重构的重要机制，而脂肪分化功能障碍是脂肪结构改变及分泌功能紊乱的主要原因。申请人前期测序结果发现房颤患者心包液外泌体内miR-548ay-3p表达上调，促脂肪分化的转录因子过氧化物酶体增殖激活受体（PPAR-γ）是其潜在的靶基因。故本项目提出科学假说：心包液外泌体内上调的miR-548ay-3p通过靶向抑制PPAR-γ调控脂肪分化，影响心房结构重构的发生。本项目拟分别在房颤患者临床样本及原代细胞等水平上检测房颤时EAT脂肪分化能力及分泌功能的改变，利用犬心包内转染模型阐明miR-548ay-3p对EAT内PPAR-γ表达及EAT脂肪分化、分泌功能的作用及其影响机制。探索通过调节EAT结构、功能缓解心房结构重构及治疗房颤的新方法。

Atrial fibrillation (AF) increases the risk of embolism and heart failure. Epicardial adipose tissue (EAT) from patients with AF exhibited adipocyte hypertrophy, interstitial fibrosis, and dysregulation of adipocytokine secretion. Atrial structural remodeling in patients with AF could be induced or exacerbated by the changes in structure and adipocytokines of EAT, which are mainly mediated through the differentiation of preadipocyte. We found that the expression level of miR-548ay-3p in exosomes from the pericardial fluid of patients with AF was higher than that of patients without AF. The TargetScan database indicates that peroxisome proliferators-activated receptor (PPAR)-γ as a key transcription factor that mediates the differentiation of preadipocytes might be the target gene of miR-548ay-3p. Thus, we hypothesize that the upregulation of miR-548ay-3p in exosomes from pericardial fluid regulates atrial structural remodeling by inhibiting PPAR-γ in EAT. In this study, the differentiation and secretion of EAT from patients with AF were analyzed using human samples and primary preadipocytes of EAT. The intrapericardial miR-548ay-3p delivery canine model will be established to investigate the roles of miR-548ay-3p in expression of PPAR-γ, differentiation of EAT, and secretion of adipocytokines in EAT. Finally, the canine model will be used to explore a new approach to alleviating atrial structural remodeling by regulating the function of EAT.