Identification of Key Genes Associated with Endothelial Cell Dysfunction in Atherosclerosis Using Multiple Bioinformatics Tools.

Guofu Zhang,Hui Yu,Lide Su,Ying Zheng,Fenglin Wang,Baodong Xie,Jingjing Su,Kai Kang,Chao Chi

doi:10.1155/2022/5544276

Abstract

Atherosclerosis is the most notable cardiovascular disease, the latter being the main cause of death globally. Endothelial cell dysfunction plays a major role in the pathogenesis of atherosclerosis. However, it is currently unclear which genes are involved between endothelial cell dysfunction and atherosclerosis. This study was aimed at identifying these genes. Based on the GSE83500 dataset, the quantification of endothelial cell function was conducted using single-sample gene set enrichment analysis; the coexpression modules were conducted using weighted correlation network analysis. After building module-trait relationships, tan and yellow modules were regarded as hub modules. 10 hub genes from each hub module were identified by the protein-protein interaction network analysis. The key genes (RAB5A, CTTN, ITGB1, and MMP9) were obtained by comparing the expression differences of the hub gene between atherosclerotic and normal groups from the GSE28829 and GSE43292 datasets, respectively. ROC analysis showed the diagnostic value of key genes. Moreover, the differential expression of key genes in normal and atherosclerotic aortic walls was verified. In vitro, we establish a model of ox-LDL-injured endothelial cells and transfect RAB5A overexpression and shRNA plasmids. The results showed that overexpression of RAB5A ameliorates the proliferation and migration function of ox-LDL-injured endothelial cells, including the ability of tubule formation. It was speculated that the interferon response, Notch signaling pathways, etc. were involved in this function of RAB5A by using gene set variation analysis. With the multiple bioinformatics analysis methods, we detected that yellow and tan modules are related to the abnormal proliferation and migration of endothelial cells associated with atherosclerosis. RAB5A, CTTN, ITGB1, and MMP9 can be used as potential targets for therapy and diagnostic markers. In vitro, overexpression of RAB5A can ameliorate the proliferation and migration function of ox-LDL-injured endothelial cells, and the possible molecules involved in this process were speculated.

Highlights

Having multiple pathogenic factors, cardiovascular disease is an important cause of death worldwide [1, 2]
It can be seen that the migration number of cells in the Human coronary artery endothelial cells (HCAECs)-RAB5A overexpression group was higher than that in HCAEC and HCAEC-RAB5A shRNA
The tube formation assay was performed to confirm that the increased expression of RAB5A can promote angiogenesis of HCAECs

Summary

Introduction

Cardiovascular disease is an important cause of death worldwide [1, 2]. Endothelial cell dysfunction (ECD) encompasses all maladaptive changes in the functional phenotype of endothelial cells and can lead to the earliest detectable changes in the course of atherosclerosis, that is, the local infiltration, capture, and chemical modification of circulating lipoprotein particles in the subendothelial space [4, 5]. Zhang et al [9] found the essential roles of the E2F1/ SNHG7/miR-186-5p/MMP2 axis in the proliferation and migration of endothelial cells, which provides a potential therapeutic target for atherosclerosis. The emergence of single-sample gene set enrichment analysis (ssGSEA), weighted correlation network analysis (WGCNA), and Molecular Signatures Database makes this attempt possible

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