Integrated Analysis of the microRNA–mRNA Network Predicts Potential Regulators of Atrial Fibrillation in Humans

Atrial fibrillation (AF) is a form of sustained cardiac arrhythmia and microRNAs (miRs) play crucial roles in the pathophysiology of AF. To identify novel miR-mRNA pairs, we performed RNA-seq from atrial biopsies of persistent AF patients and non-AF patients with normal sinus rhythm (SR). Differentially expressed miRs (11 down and 9 up) and mRNAs (95 up and 82 down) were identified and hierarchically clustered in a heat map. Subsequently, GO, KEGG, and GSEA analyses were run to identify deregulated pathways. Then, miR targets were predicted in the miRDB database, and a regulatory network of negatively correlated miR-mRNA pairs was constructed using Cytoscape. To select potential candidate genes from GSEA analysis, the top-50 enriched genes in GSEA were overlaid with predicted targets of differentially deregulated miRs. Further, the protein-protein interaction (PPI) network of enriched genes in GSEA was constructed, and subsequently, GO and canonical pathway analyses were run for genes in the PPI network. Our analyses showed that TNF-α, p53, EMT, and SYDECAN1 signaling were among the highly affected pathways in AF samples. SDC-1 (SYNDECAN-1) was the top-enriched gene in p53, EMT, and SYDECAN1 signaling. Consistently, SDC-1 mRNA and protein levels were significantly higher in atrial samples of AF patients. Among negatively correlated miRs, miR-302b-3p was experimentally validated to suppress SDC-1 transcript levels. Overall, our results suggested that the miR-302b-3p/SDC-1 axis may be involved in the pathogenesis of AF.