AMPK信号通路调控细胞自噬在心房颤动中的作用及机制

新近有报道和我们前期研究均发现，房颤患者心房肌细胞自噬水平明显增加。我们还观察到，心房快速起搏诱发房颤犬心房肌细胞自噬水平随起搏时间延长进行性显著增加，细胞自噬关键调控分子AMPK磷酸化水平明显升高；在体给予雷帕霉素诱导心房肌细胞自噬后，房颤诱发率显著增加，可被自噬抑制剂逆转。但心房肌细胞自噬在房颤发生中的作用和形成机制仍不完全清楚。因此，我们提出假设：AMPK信号通路激活诱导心房肌细胞自噬在房颤发生发展中发挥重要促进作用。本项目将从三方面阐明AMPK通路-自噬-房颤的关系：①进一步验证房颤时心房肌细胞自噬变化情况；②揭示AMPK信号通路对房颤时心房肌细胞自噬的调控作用；③阐明心房肌细胞自噬促进房颤发生和持续的作用及机制。本项目拟从在体和细胞水平，采用形态学、分子生物学和电生理学等技术，并应用AMPK基因敲除小鼠模型，从细胞自噬这一新视角深入揭示房颤发生的新机制，为临床房颤防治提供新靶点。

Autophagy was observed significantly increased in atrial myocytes of atrial fibrillation (AF) patients based on recent clincial investigation and our previous study. We found that autophagy was markedly increased in rapid atrial pacing induced AF canine model with time-dependent manner. Meanwhile the phosphorylation expression of the key signaling factor-AMPK was significantly increased. Furthermore, AF incidence was markedly elevated after inducing autophagy with rapamycin, which could be reversed by the inhibitor of autophagy. However, the occurrence of autophagy and its potential roles and mechamisms in AF remain unclear. Therefore, we hypothesize that AMPK signaling pathway induced autophagy may be a novel important molecular mechanism in the happen and maintenance of AF. This project was aimed to elucidate the relationship among AMPK pathway, autophagy and AF by the following three experimental parts. First of all, clarify the changes of autophagy in AF. Secondly, uncover the mechanisms of AMPK signaling pathway regulating autophagy in AF. Finally, validate the roles and mechanisms of autophagy aggravating the occurrence and maintenance of AF. Morphology, molecular biology and electrophysiology as well as AMPK knockout mice are employed both in vivo and in vitro to reveal a novel mechanism and target for the prevention and cure of AF from the new perspective of autophagy.