MicroRNAs in atrial fibrillation target genes in structural remodelling

• Published in: Cell and tissue research 2023-12, Vol.394 (3), p.497-514
• Main Authors: van den Berg, Nicoline W. E., Kawasaki, Makiri, Nariswari, Fransisca A., Fabrizi, Benedetta, Neefs, Jolien, van der Made, Ingeborg, Wesselink, Robin, van Boven, Wim Jan P., Driessen, Antoine H. G., Jongejan, Aldo, de Groot, Joris R.
• Format: Article
• Language: English
• Subjects: Atrial fibrillation; Atrial Fibrillation - genetics; Biomedical and Life Sciences; Biomedicine; Cardiac arrhythmia; Cell migration; Cell proliferation; Down-regulation; Endothelial cells; Epithelial-Mesenchymal Transition - genetics; Extracellular matrix; Fibrillation; Gene expression; Genes; Glycoproteins; Glycosaminoglycans; Heart Atria - metabolism; Human Genetics; Humans; Messenger RNA; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Molecular Medicine; Proteoglycans; Proteomics; Regular Article; RNA sequencing; RNA, Messenger; Stem cells
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-023-03823-0

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.