Bioinformatic Exploration of Hub Genes and Potential Therapeutic Drugs for Endothelial Dysfunction in Hypoxic Pulmonary Hypertension

Abstract

Hypoxic pulmonary hypertension (HPH) is a fatal chronic pulmonary circulatory disease, characterized by hypoxic pulmonary vascular constriction and remodeling. Studies performed to date have confirmed that endothelial dysfunction plays crucial roles in HPH, while the underlying mechanisms have not been fully revealed. The microarray dataset GSE11341 was downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between hypoxic and normoxic microvascular endothelial cell, followed by Gene Ontology (GO) annotation/Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis, and protein-protein interaction (PPI) network construction. Next, GSE160255 and RT-qPCR were used to validate hub genes. Meanwhile, GO/KEGG and GSEA were performed for each hub gene to uncover the potential mechanism. A nomogram based on hub genes was established. Furthermore, mRNA-miRNA network was predicted by miRNet, and the Connectivity Map (CMAP) database was in use to identify similarly acting therapeutic candidates. A total of 148 DEGs were screened in GSE11341, and three hub genes (VEGFA, CDC25A, and LOX) were determined and validated via GSE160255 and RT-qPCR. Abnormalities in the pathway of vascular smooth muscle contraction, lysosome, and glycolysis might play important roles in HPH pathogenesis. The hub gene-miRNA network showed that hsa-mir-24-3p, hsa-mir-124-3p, hsa-mir-195-5p, hsa-mir-146a-5p, hsa-mir-155-5p, and hsa-mir-23b-3p were associated with HPH. And on the basis of the identified hub genes, a practical nomogram is developed. To repurpose known and therapeutic drugs, three candidate compounds (procaterol, avanafil, and lestaurtinib) with a high level of confidence were obtained from the CMAP database. Taken together, the identification of these three hub genes, enrichment pathways, and potential therapeutic drugs might have important clinical implications for HPH diagnosis and treatment.