miR-101a-3p overexpression prevents acetylcholine-CaCl2-induced atrial fibrillation in rats via reduction of atrial tissue fibrosis, involving inhibition of EZH2

Abstract

Atrial fibrillation (aF), a clinically common heart arrhythmia, can result in left ventricular hypofunction, embolism and infarction. Microrna (mir)-101a-3p is lowly expressed in atrial tissues of patients with aF, but its role in aF remains unknown. in the present study, an aF model in rats was established via intravenous injection of acetyl- choline (ach)-cacl2. The downregulation of mir-101a-3p and upregulation of enhancer of zeste 2 homolog 2 (eZH2) were observed in aF model rats, indicating the involvement of mir-101a-3p and eZH2 in aF development. To study the effect of mir-101a-3p on aF in vivo, aF model rats were intra- myocardially injected with lentivirus expressing mir-101a-3p. electrocardiogram analysis identified that mir-101a-3p overexpression restored disappeared P wave and r-r inter- phase changes in ach-cacl2-induced rats. overexpression of mir-101a-3p also increased the atrial effective refractory period, reduced aF incidence and shortened duration of aF. Histological changes in atrial tissues were observed after H&e and Masson staining, which demonstrated that mir-101a-3p reduced atrial remodeling and fibrosis in aF model rats. Moreover, eZH2 expression was downregulated in atrial tissues by mir-101a-3p induction. immunohistochemistry for collagen Ⅰ and collagen III revealed a reduction in atrial collagen synthesis following mir-101a-3p overexpression in aF model rats. additionally, mir-101a-3p lowered the expres- sion of pro-fibrotic biomarkers, including TGF-β1, connective tissue growth factor, fibronectin and α-smooth muscle actin. The luciferase reporter assay results also indicated that eZH2 was a target gene of mir-101a-3p. Taken together, it was found that mir-101a-3p prevented aF in rats possibly via inhibition of collagen synthesis and atrial fibrosis by targeting EZH2, which provided a potential target for preventing aF.