MiR-148a-3p attenuates apoptosis and inflammation by targeting CNTN4 in atherosclerosis

Abstract

Background: Atherosclerosis (AS) seriously affects human health. The role of microRNAs (miRNAs) in the pathogenesis and progression of AS has become a focus of research. Our goal was to identify the biological effect of differentially expressed miRNAs (DE-miRNAs) in AS. Methods:To analyze differentially expressed genes (DEGs), including differentially expressed mRNAs (DE-mRNAs) and DE-miRNAs, in AS by using the Gene Expression Omnibus (GEO) database and limma package. DEGs protein-protein interaction (PPI) network and functional enrichment analysis were constructed by using the search tool for the retrieval of interacting genes/proteins (STRING) database, Cytoscape software and Cytoscape plugin "ClueGO2.5.6". We established a coexpression network of dysregulated miRNAs and mRNAs to predict the function of miRNAs by using miRWalk database and Pearson correlation coefficient (PCC) analysis. Cellular experiments were used to validate the results of bioinformatics.Results: First, 69 common DEGs were obtained from datasets GSE43292 and GSE97210 using the limma package in R. Next, a DEG PPI network was constructed. Functional enrichment analysis of DEGs showed that 11 functional pathways were significantly enriched, such as positive regulation of monocyte chemotaxis.Seven common DE-miRNAs were obtained from the GSE99685 dataset and DE-mRNAs predicted miRNAs through the miRWalk database. The miRNA-mRNA network constructed using Cytoscape software suggested that miR-148a-3p targeted contactin 4 (CNTN4). Quantitative real-time polymerase chain reaction (qRT-PCR) assay results indicated that miR-148a-3p was downregulated and CNTN4 was upregulated in the THP-1 + phorbol 12-myristate 13-acetate (PMA) + oxidized low-density lipoprotein (oxLDL) group compared with the THP-1 + PMA group. qRT-PCR, flow cytometry, and ELISA found that upregulated miR-148a-3p significantly inhibited the expression of CNTN4, cell apoptosis, and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) concentrations in oxLDL-induced THP-1 macrophages. In addition, a dual-luciferase reporter assay demonstrated that CNTN4 was a target gene of miR-148a-3p.Conclusions: Overall, these findings suggested that miR-148a-3p inhibited oxLDL-induced cell apoptosis and inflammation via targeting CNTN4 in THP-1 macrophages.

iPSC-Derived Endothelial Cells Reveal LDLR Dysfunction and Dysregulated Gene Expression Profiles in Familial Hypercholesterolemia

“…SYT11 is a vesicle trafficking protein that can suppress microglial activation by inhibiting cytokine secretion and phagocytosis [60]. CNTN4, a crucial adhesion protein, is involved in T-cell activation and oxLDL-induced cell apoptosis and inflammation in THP-1 macrophages [61,62]. Thus, our data suggest that dysregulation of neuronal guidance molecules (chemoattraction and chemorepulsion) can be considered as a possible mechanism for endothelial dysfunction in LDLR mutant iPSC-EC derivatives.…”

Screening and identification of key biomarkers associated with endometriosis using bioinformatics and next generation sequencing data analysis

“…Compared to normal controls, we found 958 DEGs (including 479 up regulated genes and 479 down regulated genes). PCSK9 [48], CNTN4 [49], SEMA3A [50], SFRP4 [51], MFAP5 [52], BMP6 [53], CDH6 [54], PIEZO2 [55] and PKP2 [56] are a diagnostic markers for inflammation. PCSK9 [57], SEMA3A [58] and SFRP4 [59] are associated with pain.…”

“…The expression of PCSK9 [69], SFRP4 [70] and BMP6 [71] were altered in the polycystic ovarian syndrome. Altered expression of PCSK9 [72], CNTN4 [49], SEMA3A [73], SFRP4 [74], MFAP5 [75], BMP6 [76], PDE1C [77] and PKP2 [78] promotes the development of cardiovascular diseases. PCSK9 [79], APCDD1 [80], SFRP4 [81], MFAP5 [82] and PKP2 [83] are associated to the risk of obesity.…”

Cardiovascular Disease and miRNAs: Possible Oxidative Stress-Regulating Roles of miRNAs

“…Human atherosclerosis [200] I/R injury in rats [199] 7 PDK4 [199] Increased oxidative stress by increasing 8 PDH phosphorylation while decreasing the activity of 9 PDC [204,207] 10 SESN2 [201] Alleviate oxidative stress by activating Nrf2 signaling and, thus, counteracting ROS production [209] miR-199 11 CABG surgery patients [210] SIRT1 [211] 12 BRG1 [212] Enhanced antioxidant response via deacetylation of FOXO3a [107] Enhanced Nrf2 expression and subsequent HO-1 expression [216] miR-204…”