Role of miR-146b-5p in Atrial Fibrillation–Induced Atrial Remodeling

Background: Atrial fibrillation (AF) is accompanied with structural remodeling. Profibrotic signals lead to interstitial fibrosis, which is considered a structural basis for the development, maintenance, and progression of AF. The development and maintenance of interstitial fibrosis involves expressional changes in cardiac microRNAs (miRNAs).

Method: We compared miRNA expression in right and left atrial tissue (RA, LA) between 109 patients with paroxysmal (n = 38) or persistent (n = 71) AF and 20 patients with sinus rhythm (SR) by microarray and qPCR. Among the differentially affected miRNAs, we identified miR-146b-5p as the only miRNA downregulated in AF patients. In vitro studies in human cardiac fibroblasts were performed to elucidate the role of miR-146b-5p in atrial remodeling.

Results: Mature miR-146b-5p was significantly reduced in the RA of AF patients, an effect observed in fibroblasts but not in cardiomyocytes or endothelial cells. Fibroblast proliferation and migration were inhibited after miR-146b-5p but inhibited by miR-146b-5p inhibitors. The lncRNA MALAT1, which has been reported to act as a miR-146b-5p sponge, was upregulated in AF fibroblast. Mediators involved in cardiac fibrosis such as TGF-β1 or angiotensin-II were able to induce the expression of MALAT-1 in cardiac fibroblasts, resulting in a concomitant downregulation of miR-146b-5p. Among the many predicted miR-146b-5p targets, we identified SIAH2 and EGFR by reported gene assays, qPCR and Western blots utilizing miR-146b-5p mimics or inhibitors. Finally, we show that signaling cascades such as ERK or AMPK activated by these miR-146b-5p targets are involved in altered cardiac fibroblast proliferation, migration, or cell cycle progression.

Conclusion: Altered miRNA expression occurs in AF and is involved in atrial remodeling. Understanding the precise role of altered noncoding RNA expression may provide novel therapeutic targets to interfere with the development, progression, and maintenance of AF.

Publication History

Article published online:
28 January 2023