Although some studies have shown that autophagy is involved in the occurrence and development of AF, ARGs have not been comprehensively analyzed to explore its clinical significance. In the present study, we used bioinformatics tools to analyze the integrated data of gene expression profiles from two GEO datasets to identify key ARGs related to the therapeutic targets of AF patients. We found that 11 ARGs (CDKN1A, CXCR4, DIRAS3, HSP90AB1, ITGA3, PRKCD, TP53INP2, DAPK2, IFNG, PTK6, TNFSF10) under the criteria of [log2 (fold change)] > 0.5 and P < 0.05 were differentially expressed in AF patient myocardial tissue samples. Furthermore, we also found several important pathways, suggesting that these pathways may play an important role in the mechanism of AF.
CXCR4 is found on chromosome 2q22.1 and encodes a CXC chemokine receptor specific for stromal cell-derived factor-1. Upadhye et al. [20] indicated that CXCR4 is over-expressed in humans with low coronary artery plaque burden. The interaction between CXCL12 and CXCR4 can inhibit ABCA1-dependent cholesterol efflux from macrophages, aggravating atherosclerosis [21]. The role of CXCR4 in AF is unclear. In this study, we found that CXCR4 is highly expressed in the myocardial tissue of AF patients.
Our study revealed that CDKN1A, DIRAS3, HSP90AB1, ITGA3 and PRKCD expression levels were all up-regulated in AF samples compared to control samples. CDKN1A is located on chromosome 6p21 and encodes a potent cyclin-dependent kinase inhibitor. This gene mainly plays an important role in cellular metabolic pathways [22]. DIRAS3, located on chromosome 1p31, encodes a member of the ras superfamily. The protein may play an autophagy effect in some cancer cells by regulating the autophagosome initiation complex [23]. HSP90AB1 encodes a member of the heat shock proteins 90 family; these proteins are involved in protein folding and degradation and signal transduction. The 90 kDa heat-shock protein encoded by this gene is thought to play an important role in inflammation. ITGA3 encodes a member of the integrin alpha chain family of proteins. PRKCD is located on chromosome 3p21 and encodes a member of the protein kinase C family of serine- and threonine-specific protein kinases. The protein can positively or negatively regulate apoptosis [24]. However, the relationship between these genes and cardiovascular disease has not been studied yet. Functional enrichment analyses in the present study indicated that CDKN1A, CXCR4, DIRAS3, HSP90AB1 and PRKCD were all enriched in GO terms (biological processes) of regulation of protein phosphorylation, protein kinase activity and kinase activity.
TP53INP2 is located on chromosome 20q11.22. The protein encoded by this gene is crucial in the formation and processing of autophagosomes [25]. DAPK2 is located on chromosome 15q22.31 and encodes a protein that belongs to the serine/threonine protein kinase family. Overexpression of this gene was shown to induce cell apoptosis [26]. KEGG pathway enrichment analysis showed that PRKCD, TP53INP2 and DAPK2 were enriched in the autophagy pathway. Therefore, it is extremely necessary to have a more thorough understanding of the role of these three genes in the autophagy pathway in the occurrence and development of AF.
IFNG is located on chromosome 12q15 and encodes a soluble cytokine that is a member of the type II interferon class. The encoded protein is secreted by cells of the innate immune system and the adaptive immune system. In the Framingham heart study, IFNG was significantly associated with a higher body mass index (BMI) [27]. A study published in 2015 by Barsova et al. showed that the genetic effect of IFNG and/or its biallelic combination on myocardial infarction was discovered and replicated in Russians [28]. In this study, we found that the IFNG expression level was down-regulated in the myocardial tissue of AF patients. These results revealed that IFNG was related with cardiovascular disease and might be a potential biomarker of AF.
Besides, we also screened out the other two genes PTK6 and TNFSF10. Similarly, no one has reported their relationship with cardiovascular disease before. PTK6 encodes a cytoplasmic non-receptor protein kinase that can be used as an intracellular signal converter in epithelial tissue. Akt plays an important role in the cardiovascular system, and the PTK6 metabolic pathway is an atypical pathway that affects the activity of Akt [29]. TNFSF10 is located on chromosome 3q26.31, the protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. The binding of this protein to the receptor has been shown to trigger the activation of MAPK8/JNK, caspase 8 and caspase 3 [30]. Like the IFNG, the expressions of these two genes were down-regulated in AF patients.
In the current study, we discussed 11 potential crucial DEARGs involved in the occurrence and development of AF, suggesting that these genes may serve as potential biomarkers and therapeutic targets for AF. However, there are still some limitations in this study. Firstly, our study was mainly conducted using patient data available in public database. These findings need to be verified in clinical trials. In addition, the mechanisms of ARGs regulating the initiation and progression of AF need to be further validated by RT-qPCR in clinical samples. Finally, the working mechanism of these genes is not yet fully understood, so more evidence is needed to discover its biological basis.