As a disease with high morbidity, AF is a major public cardiac healthy concern, which causes a high incidence of thrombosis . Although scientists have made prodigious progress in the treatments of AF including the reduction of symptoms, the control of rate, the prevention of thromboembolism and cardiomyopathy, the awareness of accurate molecular mechanisms of AF remains suboptimal.
We integrated three publicly available gene-related AF datasets with bioinformatics analysis. We identified 264 DEGs, of which expression of 179 was upregulated and 65 was downregulated. Besides, 40 DEGs were uncovered in miRNA-related AF microarray data and 2383 DEGs were sorted using the miRTarbase database. Furthermore, the intersection of DEGs was constructed and 26 CDEGs were uncovered.
Studies have shown that activation of the PI3K-Akt signaling pathway promotes the growth and proliferation of cells, inhibits apoptosis, reduces blood glucose levels, enhances the inflammatory response, and aggravates the vulnerability of unstable atherosclerotic plaques.
Jalife and colleagues discovered that the interaction between AF and atrial remodeling leads to arrhythmia exacerbation . McMullen and collaborators found that inhibition of the PI3K-Akt signaling pathway could increase AF incidence . Xue and coworkers showed that exogenous hydrogen sulfide might be helpful for reduction of the atrial remodeling and AF caused by diabetes mellitus through activation of the PI3K/Akt/endothelial nitric oxide pathway . Zhao and collaborators postulated that aliskiren might upregulate expression of the PI3K/Akt pathway to exert cardioprotective effects against rapid atrial pacing . Taken together, these results suggest that regulation of the PI3K-Akt signaling pathway might participate in AF progression. Cardiac fibrosis occupies an important position in cardiac remodeling, which is consistent with AF .
Zhang and coworkers demonstrated that c-MYC expression was upregulated by lncRNA ROR and facilitated the proliferation and differentiation of cardiac fibroblasts . Moreover, MYC could be an important molecule downstream of the PI3K/Akt signaling pathway in various tumors . DDIT4 has been shown to be activated under stress situations . Li and colleagues demonstrated that DDIT4 mediates methamphetamine-induced autophagy and apoptosis through the mammalian target of rapamycin (mTOR) signaling pathway in cardiomyocytes . HSP90AB1 supports the appropriate folding and maintenance of stability of proteins . García and colleagues verified that HSP90AB1-TGFβ receptor I complex is an active participant in collagen production in TGF-β-activated fibroblasts . Based on our results, we speculate that MYC, DDIT4, and HSP90AB1 might function in AF progression through the PI3K-Akt signaling pathway.
We constructed an miRNA-TFs-target regulatory network. miRNAs and TFs function as regulators of expression of target genes [40, 41]. In most cases, miRNA inhibits expression of the target gene, so we were more focused on “reverse-regulated” miRNA–mRNA pairs. With the combination of “hub” genes, four pairs were visualized. Of these, superoxide dismutase 2 (SOD2) dominated the pairs. SOD2 is a mitochondrial antioxidant enzyme. Xu and colleagues found the protein expression of SOD2 was upregulated in AF rats after treatment with the proliferator-activated receptor-γ activator pioglitazone: those data are consistent with our findings . miRNAs related to SOD2 included miRNA-671-5p, miRNA-4306, miRNA-3125 and miRNA-4298.
Numerous studies have shown that the function of miRNA-671-5p varies in different types of cancer, including inhibition of cell proliferation, transformation and promotion of apoptosis in gastric cancer, breast cancer, osteosarcoma, and esophageal squamous cell carcinoma [43-46], but the reverse functions in colon cancer . miR-4306 has been shown to be related to triple-negative breast cancer . Wang and collaborators found that miRNA-4298 expression in glioblastoma patients differed from that in healthy cohorts. Little research has been undertaken on miRNA-3125 until now .
With regard to TFs, with the combination of genes enriched in the PI3K-Akt signaling pathway, hypoxia-inducible factor 1 (HIF1)a and signal transducer and activator of transcription 1 (STAT1) were found to be associated with HSP90AB1 and MYC. HIF1a expression has been shown to increase in the right atrial appendages of AF patients . Tsai and coworkers demonstrated STAT1 to be activated in pigs with AF .
Our study had three main limitations. First, we concentrated only on reverse regulation of miRNA–mRNA pairs and ignored the more complicated mechanisms of miRNA–mRNA pairs, Second, the miRNA and mRNA we obtained were not from identical samples. Finally, we concentrated on public databases: in vitro and in vivo studies are required to validate our findings.