LncRNA Dleu2 Serve as a Novel Biomarker for Ablation Recurrence and Promote Atrial Remodelling by Targeting Nr4a1 in Atrial Fibrillation

Abstract

Atrial remodelling is the principal pathological mechanism for atrial fibrillation (AF) development and progression. Long noncoding RNAs (LncRNAs) exhibit important effects on cardiovascular diseases. However, the role of LncRNAs in AF development requires further investigation. This study aimed to explore the function and mechanism of LncRNAs in AF. The differentially expressed LncRNAs of atrial tissue in a mouse AF model, which was established via continuous infusion of Ang II for 3 weeks, were screened with RNA sequencing. Experiments included an electrophysiological study; Masson, H&E and TUNEL staining; flow cytometry; and RNA pull-down; FISH and RNA immunoprecipitation assays were performed to define the function and underlying mechanisms of LncRNAs in AF susceptibility and atrial remodelling. The Kaplan–Meier method was used to plot the curve of freedom from atrial tachyarrhythmia. LncRNA Dleu2 expression was increased in atrial tissue and peripheral blood and was positively associated with left atrial fibrosis in persistent AF. Furthermore, elevated expression of LncRNA Dleu2 was correlated with a higher AF recurrence rate after ablation at the 24-month follow-up (65.0% vs. 85.0%, p = 0.03). Accordingly, upregulation and downregulation of LncRNA Dleu2 expression could regulate atrial remodelling and AF susceptibility, and we also demonstrated that LncRNA Dleu2 directly bound to Nr4a1. Subsequently, inhibition of Nr4a1 expression could also regulate AF susceptibility and atrial remodelling and reverse the effects of LncRNA Dleu2 on AF occurrence. This study demonstrated that LncRNA Dleu2 was independently associated with atrial fibrosis and AF recurrence after ablation, and contributed to AF susceptibility by directly targeting Nr4a1.