miRNA-145靶向调控EPS15介导的细胞自噬参与心房颤动心房重构的机制研究

研究表明细胞自噬异常可能参与心房颤动（房颤）的发生，但机制尚未明确。Cx43重构及心房纤维化是导致房颤的重要机制。自噬过度激活可致Cx43重构，Cx43重构又可进一步激活自噬，促进心房纤维化。EPS15在这一过程中起着重要作用，并且是miRNA-145潜在的靶基因。据此我们假说，各种病因所致的miRNA-145下调，通过上调EPS15，导致自噬过度激活、Cx43重构及心房纤维化。我们将检测房颤患者和房颤犬心房miRNA-145、EPS15表达变化及其与自噬、Cx43重构、心房纤维化的关系；构建miRNA-145低/过表达的心房肌细胞和小鼠模型，观察对EPS15表达、细胞自噬、Cx43重构、心房纤维化及房颤易感性的影响，从而探讨细胞自噬异常参与房颤发生的机制，为房颤的干预提供新靶点。

Some studies revealed that autophagy overactivation contributed to atrial fibrillation(AF). However, the specific mechanism remians poorly understood.Connexin43(Cx43) and atrial fibrosis play the important roles in AF. Interestingly, autophagy over-activation could promote internalization and degradation of Cx43, while the internalization and degradation of Cx43 enhances autophagy acceleration.EPS15 thta is potential target gene of miRNA-145 plays an important role in this progress. Therefore, we hypothesize that autophagy over-activation, which downregulation of miRNA-145 mediates by targeting EPS15, enhances Cx43 remolding and atrial fibrosis, and contributes to AF. To testify.this hypothesis, the miRNA-145, EPS15, autophagy, Cx43, and collagen deposit in atrium of AF patients and chronic AF canine models will be measured. The underexpressed /overexpressed miRNA-145 mouse atrial myocyte and mouse models will be made by miRNA mimic/inhibitor transfection and lentiviral vector transfection, respectively. The effect of underexpressed or overexpressed miRNA-145 on EPS15, autophagy flux, Cx43 remolding, atrial fibrosis, and AF susceptibility will be detected.Taken together, the mechanisms that autophagy over-activation regulated by miRNA-145 involves in pathogenesis of AF will be investigated to provide novel targets for treatment of AF.