Per2调控心肌细胞自噬在β1肾上腺素受体自身抗体诱导心房纤维化及房颤中的作用机制

心房纤维化与心房颤动（房颤）发生发展密切相关。课题组前期研究发现β1肾上腺素受体自身抗体（β1ARAb）表达增强诱导心房纤维化、增加房颤易感性，但其具体机制不明。申请人通过蛋白组学等预实验进一步发现：免疫β1ARAb可导致心房肌细胞自噬降低、凋亡增加，并下调左心房Period2（Per2）及其下游蛋白PTEN表达；而Per2转染至β1ARAb孵育的HL-1细胞，可恢复β1ARAb诱导的自噬及凋亡相关蛋白的表达变化。基于前期研究证据，我们推测β1ARAb通过抑制Per2/PTEN表达、激活PI3K/AKT/mTOR信号通路、降低心肌细胞自噬，最终导致心房纤维化及房颤。本课题拟采用被动免疫兔模型及HL-1细胞，通过在体和离体层面观察双向调控Per2对β1ARAb诱导的心房电生理及心肌细胞自噬、凋亡的影响，探索β1ARAb诱导心房纤维化及房颤的分子机制，为房颤精准治疗提供新的干预靶点。

Atrial fibrosis is closely related to the occurrence and development of atrial fibrillation (AF). Our previous studies have found that the expression of β1-adrenoceptor autoantibody (β1ARAB) could increase the induction of atrial fibrosis and susceptibility to AF, but the detailed mechanism remained to be clarified. Through proteomics and other pre-experiments, the applicant further found that the immunity of β1ARAb can reduce autophagy and increase apoptosis of atrial myocytes, the protein expression of Period2 (Per2) and PTEN in the left atrium were down-regulated by β1ARAb, while the expression of autophagy and apoptosis-related proteins induced by β1ARAb could be restored by Per2 transfection into HL-1 cells incubated with β1ARAb. Based on the previous evidence, we speculate that β1ARAb activates the PI3K/AKT/mTOR signaling pathway by inhibiting the expression of Per2/PTEN, reduces autophagy in cardiomyocytes, and ultimately leads to the occurrence of AF. In this study, we use rabbit model and HL-1 cells to observe the effects of bi-directional regulation of Per2 on atrial electrophysiology and cardiomyocyte autophagy and apoptosis induced by β1ARAb in vivo and in vitro, and to explore the molecular mechanism of β1ARAb-induced atrial fibrosis and AF, and to provide a new molecular target for precise treatment of AF.