Abstract
Background Circular RNAs (circRNAs) were known to be related to the pathogenesis of many diseases through competing endogenous RNA (ceRNA) regulatory mechanisms. However, the function of circRNA in coronary artery disease (CAD) remains unclear. In this study, we aim to construct a circRNA-related competing endogenous RNA (ceRNA) network in CAD. Methods The gene expression profiles of CAD were obtained from Gene Expression Omnibus datasets. Bioinformatics analysis was performed to construct a ceRNA regulatory network, from which the hub genes involved were identified through protein-protein interaction (PPI) networks leading to the identification of the circRNA-miRNA-hub gene subnetwork. In addition, function enrichment analysis was performed to detect the potential biological mechanism in which circRNA might be involved. Results A total of 115 DEcircRNAs (differentially expressed circRNAs), 17 DEmiRNAs (differentially expressed microRNAs), and 790 DEmRNAs (differentially expressed mRNAs) were identified between CAD and control groups from microarray datasets. Functional enrichment analysis showed that DEmRNAs were significantly involved in inflammation-related pathways and ubiquitin-protein ligase binding. After identifying 20 DEcircRNA-DEmiRNA pairs and 561 DEmiRNA-DEmRNA pairs, we obtained a circRNA-miRNA-mRNA regulatory network. PPI network analysis showed that eight hub genes were closely related to CAD, leading to the identification of a circRNA-miRNA-hub gene subnetwork consisting of nine circRNAs (hsa_circ_0020275, hsa_circ_0020387, hsa_circ_0020417, hsa_circ_0045512, hsa_circ_0047336, hsa_circ_0069094, hsa_circ_0071326, hsa_circ_0071330, and hsa_circ_0085340), four miRNAs (hsa-miR-136-5p, hsa-miR-376c-3p, hsa-miR-411-5p, and hsa-miR-654-5p), and eight mRNAs (MKRN1, UBE2H, UBE2W, UBE2D1, UBE2F, BE2J1, ZNRF1, and SIAH2). In addition, we discovered these hub genes were enriched in the ubiquitin-mediated proteolysis pathway, suggesting circRNAs may be involved in the pathogenesis of CAD through this pathway. Conclusions This study may deepen our understanding of the potential role of circRNA-miRNA-mRNA regulation network in CAD and suggest novel diagnostic biomarkers and therapeutic targets for CAD.
Highlights
Coronary artery disease (CAD), a cardiac disease caused by abnormal structure or function of the coronary artery, remains one of the leading causes of death and poses a heavy socioeconomic burden worldwide [1]
When multiple probes correspond to the same gene symbol, the final probe expression value is calculated by the maximum value of probes. e probes that did not match a gene symbol were deleted. e Bioconductor Limma package was used to identify the DEcircRNAs, DEmiRNAs, and DEmRNAs between CAD samples and the control samples. e criteria for selection of DEcircRNAs and DEmRNAs were P value 1 (|FC| > 2)
Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the 790 DEmRNAs identified in the previous section. e GO analysis demonstrated that the DEmRNAs were enriched in immune response (GO:0006955), inflammatory response (GO:0006954), and response to lipopolysaccharide (GO: 0032496) for biological process (BP)
Summary
Coronary artery disease (CAD), a cardiac disease caused by abnormal structure or function of the coronary artery, remains one of the leading causes of death and poses a heavy socioeconomic burden worldwide [1]. Previous studies have shown that circRNAs, as competitive endogenous RNAs (ceRNAs), can act as microRNA (miRNA) sponges with miRNA response elements (MRE), to regulate miRNA expression, thereby regulating the target genes of miRNAs and participating in the pathogenesis of CAD [6]. Bioinformatics analysis was performed to construct a ceRNA regulatory network, from which the hub genes involved were identified through protein-protein interaction (PPI) networks leading to the identification of the circRNA-miRNA-hub gene subnetwork. PPI network analysis showed that eight hub genes were closely related to CAD, leading to the identification of a circRNA-miRNA-hub gene subnetwork consisting of nine circRNAs (hsa_circ_0020275, hsa_circ_0020387, hsa_circ_0020417, hsa_circ_0045512, hsa_circ_0047336, hsa_circ_0069094, hsa_circ_0071326, hsa_circ_0071330, and hsa_circ_0085340), four miRNAs (hsa-miR-136-5p, hsa-miR-376c-3p, hsa-miR-411-5p, and hsa-miR-654-5p), and eight mRNAs (MKRN1, UBE2H, UBE2W, UBE2D1, UBE2F, BE2J1, ZNRF1, and SIAH2). Conclusions. is study may deepen our understanding of the potential role of circRNA-miRNAmRNA regulation network in CAD and suggest novel diagnostic biomarkers and therapeutic targets for CAD
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