Identification of microRNAs enriched in exosomes in human pericardial fluid of patients with atrial fibrillation based on bioinformatic analysis

Abstract

Background: Atrial fibrillation (AF) is related to structural and electrical atria remodeling. Atrial fibrosis development and progression is characteristic of structural remodeling and is taken as the AF perpetuation substrate. Increasing evidence has confirmed that microRNAs (miRNAs) are associated with AF, including cardiac fibrosis. Methods: Pericardial fluid (PF) samples were collected from nine adult patients who had congenital heart disease with persistent AF or sinus rhythm (SR) undergoing surgery. Abnormally expressed miRNAs were acquired, and P<0.05 and fold change >2 were taken as the thresholds of differentially expressed miRNAs (DE-miRNAs). The predicted target genes were obtained by miRTarBase. The Database for Annotation, Visualization and Integrated Discovery was used to annotate functions and analyze pathway abundance for latent targets of DE-miRNAs. STRING database was applied to construct a protein-protein interplay (PPI) network, and Cytoscape software was used to visualize the miRNA-hub gene-Kyoto Encyclopedia of Genes and Genomes (KEGG) network. DE-miRNA expressions were evaluated by quantitative polymerase chain reaction (qPCR).Results: Fifty-five exosomal DE-miRNAs were found between the AF and SR samples; these included 24 miRNAs that were upregulated and 31 that were downregulated. For the top 3 downregulated miRNAs (miR-382-3p, miR-3126-5p, and miR-450a-2-3p) 283 predicted target genes were identified, and were implicated in cardiac fibrosis-related pathways, including the hypoxia-inducible factor-1 (HIF1), mitogenactivated protein kinase (MAPK), and adrenergic and insulin pathways. The top 10 hub genes in the PPI network, including mitogen-activated protein kinase 1 (MAPK1) and AKT serine/threonine kinase 1 (AKT1), were identified as hub genes. By establishing the miRNA-hub gene-KEGG network, we observed that these hub genes, which were regulated by miR-382-3p, miR-3126-5p, and miR-450a-2-3p, were involved in many KEGG pathways associated with cardiac fibrosis, such as the AKT1/glycogen synthase kinsase-3β (GSK-3β) and transforming growth factor-β (TGF-β)/MAPK1 pathways. Conclusions: The findings of the present study suggest that miR-382-3p, miR-450a-2-3p, and miR-3126-5p contained in exosomes in human PF are pivotal in the progression of AF. The results of qPCR showed that miR-382-3p was consistent with our sequencing data, which indicates its potential value as a therapeutic target for AF.

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

“…These miRNAs targeted pathways related to atrial function and structure, oxidative stress, and fibrosis [ 231 ]. Similarly, EVs from pericardial fluid of atrial fibrillation patients contained 31 downregulated miRs and 24 upregulated miRs, the latter of which included miR-382-3p, -2136-5p, and 450a-2-3p which are predicted to target multiple fibrosis-related genes [ 232 ]. Plasma exosomes from heart failure patients contained elevated levels of miR-21 and reduced levels of miR-425 and miR-744 and these miRs regulated fibrogenic pathways in cardiomyocytes [ 173 , 233 ].…”

lncRNA IGF2‐AS promotes the osteogenic differentiation of bone marrow mesenchymal stem cells by sponging miR‐3,126‐5p to upregulate KLK4

“…Previously, miR‐3,126‐5p was shown to function as a diagnostic marker of hepatocellular carcinoma 23 . Another study revealed that miR‐3,126‐5p was differentially expressed in patients with atrial fibrillation 32 . Moreover, a study conducted by Azuma Y et al 33 showed that miR‐3,126‐5p participated in the process of gefitinib‐resistant lung cancer.…”

The Role of Exosomes and Their Cargos in the Mechanism, Diagnosis, and Treatment of Atrial Fibrillation

“…The studies of Wei et al and Liu et al are similar. The former study showed that expression of miR-92b-3p, miR-1306-5p and miR-let-7b-3p are different in patients with AF compared to those with normal sinus rhythm ( 55 ), while the latter identified miR-382-3p as a differentially expressed miRNA ( 56 ). The study of Mun et al attempted to identify specific biomarkers for persistent AF.…”

“…The following miRNAs have been shown to appear in exosomes and contribute to the diagnosis of AF: miR-483-5p, miR-142-5p, miR-223-3p, miR-223-5p, miR-92b-3p, miR-1306-5p and miRlet-7b-3p, miR-382-3p, miRNA-103a,−107,−320d,−486, and let-7b (50,(54)(55)(56).…”