AUTHOR=Zhao Zhengde , Fu Qining , Hu Liangzhu , Liu Yangdong 

TITLE=Identification of the Crucial Gene in Overflow Arteriovenous Fistula by Bioinformatics Analysis

JOURNAL=Frontiers in Physiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.621830

DOI=10.3389/fphys.2021.621830

ISSN=1664-042X

ABSTRACT=<p><bold>Objective:</bold> The aim was to study the preliminary screening of the crucial genes in intimal hyperplasia in the venous segment of arteriovenous (AV) fistula and the underlying potential molecular mechanisms of intimal hyperplasia with bioinformatics analysis.</p><p><bold>Methods:</bold> The gene expression profile data (GSE39488) was analyzed to identify differentially expressed genes (DEGs). We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of DEGs. Gene set enrichment analysis (GSEA) was used to understand the potential activated signaling pathway. The protein–protein interaction (PPI) network was constructed with the STRING database and Cytoscape software. The Venn diagram between 10 hub genes and gene sets of 4 crucial signaling pathways was used to obtain core genes and relevant potential pathways. Furthermore, GSEAs were performed to understand their biological functions.</p><p><bold>Results:</bold> A total of 185 DEGs were screened in this study. The main biological function of the 111 upregulated genes in AV fistula primarily concentrated on cell proliferation and vascular remodeling, and the 74 downregulated genes in AV fistula were enriched in the biological function mainly relevant to inflammation. GSEA found four signaling pathways crucial for intimal hyperplasia, namely, MAPK, NOD-like, Cell Cycle, and TGF-beta signaling pathway. A total of 10 hub genes were identified, namely, <italic>EGR1, EGR2, EGR3, NR4A1, NR4A2, DUSP1, CXCR4, ATF3, CCL4</italic>, and <italic>CYR61</italic>. Particularly, <italic>DUSP1</italic> and <italic>NR4A1</italic> were identified as core genes that potentially participate in the MAPK signaling pathway. In AV fistula, the biological processes and pathways were primarily involved with MAPK signaling pathway and MAPK-mediated pathway with the high expression of <italic>DUSP1</italic> and were highly relevant to cell proliferation and inflammation with the low expression of <italic>DUSP1</italic>. Besides, the biological processes and pathways in AV fistula with the high expression of <italic>NR4A1</italic> similarly included the MAPK signaling pathway and the pathway mediated by MAPK signaling, and it was mainly involved with inflammation in AV fistula with the low expression of <italic>NR4A1</italic>.</p><p><bold>Conclusion:</bold> We screened four potential signaling pathways relevant to intimal hyperplasia and identified 10 hub genes, including two core genes (i.e., <italic>DUSP1</italic> and <italic>NR4A1</italic>). Two core genes potentially participate in the MAPK signaling pathway and might serve as the therapeutic targets of intimal hyperplasia to prevent stenosis after AV fistula creation.</p>