circRNA/miRNA-133-3p调控FHF1促心房颤动易损基质形成及机制

心房电重构是心房颤动（AF）发生发展的基质。研究证实，纤维生长因子同源因子1（FHF1）调节Na+流导致心房电重构，miR-133-3p促心房重构与AF发生相关，而miRNA受circRNA调控。我们发现FHF1增加心肌肥厚大鼠AF易感性，FHF1与miR-133-3p表达负相关，FHF1可能是miR-133-3p的作用靶基因；再利用高通量测序人心房组织，筛选与AF相关显著差异表达的circRNA，获得调控miR-133-3p的关键circRNA。为验证circRNA、miR-133-3p和FHF1之间的关系及对AF发生的作用及机制，拟利用HL-1细胞、FHF1-/-心肌肥厚大鼠及人心房组织，通过RIP、荧光酶素报告、共聚焦、膜片钳等方法，研究circRNA参与miR-133-3p 调控 FHF1促AF易损基质形成的作用机制。从circRNA的新视点探讨AF发生机制，为AF防治提供新思路。

Atrial remodeling is the basic substrate of atrial fibrillation(AF). Fibroblast growth factor homologous factor 1 (FHF1) lead to atrial electrical remodeling by regulating Na+ currents.MiR-133-3p promotes AF occurrence by promoting atrial remodeling , and miRNA could be regulated by circRNA. We found FHF1 increased AF susceptibility in rats with myocardial hypertrophy, while miR-133-3p was negatively correlated with FHF1, which might be the direct target of miR-133-3p. We screened circRNAs which had significantly different expressions in atrial between AF patients and sinus rhythm(SR) patients by high throughput sequencing and then predicted key circRNAs regulating miR-133-3p/FHF1. To verify the regulatory effects among circRNA、miR-133-3p and FHF1 and clarify their roles and mechanisms in AF occurrence, we investigate the role and molecular mechanism of circRNA in regulating the formation of vulnerable substrate to atrial fibrillation through miR-133-3p/FHF1 by doing Luciferase assays, RIP assays immunofluorescence and patch clamp in HL-1 myocytes, FHF1-/- rats with cardiac hypertrophy and human atrial tissue. We explore the mechanism of AF in the novel vision of circRNA, which provides new perspective in the prevention and treatment of AF.