We aim to elucidate how miRNAs regulate the mRNA signature of atrial fibrillation (AF), to gain mechanistic insight and identify candidate targets for future therapies. We present combined miRNA–mRNA sequencing using atrial tissues of patient without AF (n = 22), with paroxysmal AF (n = 22) and with persistent AF (n = 20). mRNA sequencing previously uncovered upregulated epithelial to mesenchymal transition, endothelial cell proliferation and extracellular matrix remodelling involving glycoproteins and proteoglycans in AF. MiRNA co-sequencing discovered miRNAs regulating the mRNA expression changes. Key downregulated miRNAs included miR-135b-5p, miR-138-5p, miR-200a-3p, miR-200b-3p and miR-31-5p and key upregulated miRNAs were miR-144-3p, miR-15b-3p, miR-182-5p miR-18b-5p, miR-4306 and miR-206. MiRNA expression levels were negatively correlated with the expression levels of a multitude of predicted target genes. Downregulated miRNAs associated with increased gene expression are involved in upregulated epithelial and endothelial cell migration and glycosaminoglycan biosynthesis. In vitro inhibition of miR-135b-5p and miR-138-5p validated an effect of miRNAs on multiple predicted targets. Altogether, the discovered miRNAs may be explored in further functional studies as potential targets for anti-fibrotic therapies in AF.

我们的目标是阐明 miRNA 如何调节心房颤动 (AF) 的 mRNA 特征，以获得机制见解并确定未来治疗的候选靶点。我们使用无 AF ( n  = 22)、阵发性 AF ( n  = 22) 和持续性 AF ( n  = 20) 患者的心房组织进行 miRNA-mRNA 联合测序。mRNA 测序先前发现 AF 中涉及糖蛋白和蛋白聚糖的上皮间质转化、内皮细胞增殖和细胞外基质重塑上调。miRNA 共测序发现 miRNA 调节 mRNA 表达变化。关键下调的 miRNA 包括 miR-135b-5p、miR-138-5p、miR-200a-3p、miR-200b-3p 和 miR-31-5p，关键上调的 miRNA 包括 miR-144-3p、miR-15b-3p、 miR-182-5p、miR-18b-5p、miR-4306 和 miR-206。miRNA 表达水平与多种预测靶基因的表达水平呈负相关。与基因表达增加相关的下调 miRNA 参与上皮细胞和内皮细胞迁移以及糖胺聚糖生物合成的上调。miR-135b-5p 和 miR-138-5p 的体外抑制验证了 miRNA 对多个预测靶标的影响。总而言之，所发现的 miRNA 可以作为 AF 抗纤维化治疗的潜在靶点在进一步的功能研究中进行探索。