MicroRNA-21通过调控心外膜脂肪棕色化参与糖尿病致心房纤维化的机制研究

Diabetes mellitus (DM) is one of the major risk factors for the occurrence of atrial fibrillation(AF) by acting on atrial fibrosis mechanisms. By releasing pro-inflammatory cytokines and adipokines, epicardial adipose tissue (EAT) contributes to the process of atrial fibrosis. And the browning of white adipose in EAT might mitigate the process of atrial fibrosis induced by DM. It has been proved that peroxisome proliferator-activated receptor γ (PPARγ)/fibroblast growth factor 21 (FGF21) signaling pathway facilitates the browning of white adipose through activating the complex of fibroblast growth factor receptor 1 (FGFR1)- β-Klotho. And the current research group observed that miR-21 expression induced by high glucose inhibited the browning of EAT, which might be associated with its negative regulating of FGFR1. Therefore, we put forward the hypothesis that high glucose activates miR-21 expression in EAT, negatively regulates the expression of FGFR1, then contributes to the inhibitory effect of PPARγ/FGF21/FGFR1-β-Klotho signaling pathway and browning of EAT, which results in the pathogenesis of atrial fibrosis. Through establishing DM-induced atrial fibrosis model in vitro and in vivo, and using experimental methods, such as cell co-culture, gene knockout and electrophysiological techniques, etc, we are going to evaluate the role of miR-21 in the process of the EAT browning and DM-induced atrial fibrosis. These findings will provide novel molecular mechanisms involved in DM-induced atrial fibrosis.

糖尿病致心房纤维化是糖尿病患者发生房颤的主要原因，心外膜脂肪组织(EAT)依靠旁分泌炎性和脂肪细胞因子参与心房纤维化过程，而促进EAT中白色脂肪棕色化可能抑制糖尿病致心房纤维化进程。已证实PPARγ/FGF21通过活化FGFR1-β-Klotho复合体促进白色脂肪棕色化，而本课题组前期工作观察到高糖诱导的miR-21表达上调可抑制EAT棕色化过程，且其机制可能与负性调控FGFR1有关。本项目由此提出假设：高糖可能通过上调EAT中miR-21表达、负性调控FGFR1表达，从而抑制PPARγ/FGF21/FGFR1-β-Klotho信号轴活化，减弱EAT棕色化，加重心房纤维化的发生。本项目拟复制在体和离体糖尿病致心房纤维化模型，采用细胞共培养、基因敲除、电生理等实验方法，探讨miR-21调控EAT棕色化的分子机制及其在糖尿病致心房纤维化中的作用，进一步完善糖尿病致心房纤维化的分子机制。

糖尿病是房颤、心力衰竭的重要危险因素，其机制与高血糖环境下心肌细胞损伤有关。近期研究提示高血糖环境导致的脂肪组织重构参与糖尿病致心肌损伤，本项目深入探讨其机制及开展相关临床研究，取得如下研究结果：第一，通过体内外实验提示高糖环境下，miR-21亚家族成员miR-21-3p可通过负性调控FGFR1，抑制FGFR1/FGF21/PPARγ信号通路活化导致的心外膜脂肪细胞棕色化过程，同时促进其炎性细胞因子分泌，进而导致糖尿病致心房纤维化的发生。第二，通过体内外实验提示高血糖可促进脂肪组织衰老，进而通过旁分泌及内分泌作用促进心肌细胞病理性重构，损伤其舒张和收缩功能，导致心脏舒张功能不全的发生；第三，糖尿病导致的心房纤维化/房颤与肾素－血管紧张素－醛固酮系统激活有关，ACE2过表达可改善实验犬模型中心房电重构和心房功能，其机制可能与抑制TRPM7信号通路有关。第四，小样本前瞻随机对照临床研究提示PPARγ激动剂吡格列酮可减轻持续性房颤合并2型糖尿病患者电复律术后炎症水平，但其并不能减少随访期内的房颤复发。第五，队列研究提示2型糖尿病患者长期血糖变异性升高是新发房颤及射血分数保留心力衰竭的独立危险因素，且血糖变异性升高也是2型糖尿病合并心力衰竭患者发生不良心血管事件的独立危险因素。第六，倾向性匹配分析提示，2型糖尿并合并高血压患者长期应用二甲双胍治疗，新发射血分数保留心力衰竭明显低于非二甲双胍组,二甲双胍治疗能更明显的改善左室肥厚及左室舒张功能，而且二甲双胍治疗是射血分数保留心力衰竭发生的独立保护性因素。本项研究提示高血糖导致脂肪组织重构参与心肌损伤过程，其机制涉及抑制心外膜脂肪棕色化和促进外周脂肪组织衰老，深入其机制研究可能获得干预糖尿病致心肌损伤的新靶点；其次，糖尿病患者长期血糖变异性升高与新发房颤或射血分数保留心力衰竭，乃至心衰临床预后密切相关，临床工作中应予以关注。