scholarly journals Essential genes and miRNA-mRNA network contributing to the pathogenesis of idiopathic pulmonary arterial hypertension

2020 ◽  
Author(s):  
Shengyu Hao ◽  
Pan Jiang ◽  
Liang Xie ◽  
Guiling Xiang ◽  
Zilong Liu ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
Functional Module ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Leukocyte Migration ◽  
Differentially Expressed ◽  
Functional Modules ◽  
Hub Genes ◽  
Pulmonary Arterial

Abstract Background: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease. Owing to its high fatality rate and narrow therapeutic options, identification of the pathogenic mechanisms of IPAH is becoming increasingly important.Methods: In our research, we utilized the Robust Rank Aggregating (RRA) method to integrate four eligible PAH microarray datasets and identified the significant differentially expressed genes (DEGs) between IPAH and normal samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed to analyze their functions. The interaction network of protein-protein internet (PPI) was constructed to explore the correlation between these DEGs. The functional modules and hub genes were further identified by the weighted gene coexpression network analysis (WGCNA). Moreover, a miRNA microarray dataset was involved and analyzed to filter differentially expressed miRNA (DE-miRNAs). Potential target genes of screened DE-miRNAs were predicted and merged with DEGs to explore a miRNA-mRNA network in IPAH. Some hub genes were selected and validated by RT-PCR in lung tissues from PAH animal model.Results: A total of 260 DEGs, consisting of 183 upregulated and 77 down-regulated significant DEGs were identified, and some of those genes were novel. Their molecular roles in the etiology of IPAH remained vague. The most crucial functional module involved in IPAH mainly enriched in biological processes, including leukocyte migration, cell chemotaxis, and myeloid leukocyte migration. Construction and analysis of the PPI network showed that CXCL10, CXCL9, CCR1, CX3CR1, CX3CL1, CXCR2, CXCR1, PF4, CCL4L1, and ADORA3 were recognized as top10 hub genes with high connectivity degrees. WGCNA further identified five main functional modules involved in the pathogenesis of IPAH. 12 upregulated DE-miRNAs and 9 downregulated DE-miRNAs were identified. Among them, four downregulated DEGs, and eight upregulated DEGs were supposed to be negatively regulated by three upregulated DE-miRNAs, and three downregulated DE-miRNAs, respectively.Conclusions: This study identifies some key and functional coexpression modules involved in IPAH, as well as a potential IPAH-related miRNA-mRNA regulated network. It provides deepening insights into the molecular mechanisms and provides vital clues in seeking novel therapeutic targets for IPAH.

scholarly journals Comprehensive Analyses of miRNA-mRNA Network and Potential Drugs in Idiopathic Pulmonary Arterial Hypertension

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Chan Li ◽  
Zeyu Zhang ◽  
Qian Xu ◽  
Ruizheng Shi
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Kegg Pathway ◽  
Enrichment Analysis ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Differentially Expressed ◽  
Pathway Enrichment Analysis ◽  
Ppi Network ◽  
Hub Genes ◽  
Pulmonary Arterial

Introduction. Idiopathic pulmonary arterial hypertension (IPAH) is a severe cardiopulmonary disease with a relatively low survival rate. Moreover, the pathogenesis of IPAH has not been fully recognized. Thus, comprehensive analyses of miRNA-mRNA network and potential drugs in IPAH are urgent requirements. Methods. Microarray datasets of mRNA and microRNA (miRNA) in IPAH were searched and downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMIs) were identified. Then, the DEMI-DEG network was conducted with associated comprehensive analyses including Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis, while potential drugs targeting hub genes were investigated using L1000 platform. Results. 30 DEGs and 6 DEMIs were identified in the lung tissue of IPAH. GO and KEGG pathway analyses revealed that these DEGs were mostly enriched in antimicrobial humoral response and African trypanosomiasis, respectively. The DEMI-DEG network was conducted subsequently with 4 DEMIs (hsa-miR-34b-5p, hsa-miR-26b-5p, hsa-miR-205-5p, and hsa-miR-199a-3p) and 16 DEGs, among which 5 DEGs (AQP9, SPP1, END1, VCAM1, and SAA1) were included in the top 10 hub genes of the PPI network. Nimodipine was identified with the highest CMap connectivity score in L1000 platform. Conclusion. Our study conducted a miRNA-mRNA network and identified 4 miRNAs as well as 5 mRNAs which may play important roles in the pathogenesis of IPAH. Moreover, we provided a new insight for future therapies by predicting potential drugs targeting hub genes.

scholarly journals Identification of Hub Genes and MicroRNAs Associated With Idiopathic Pulmonary Arterial Hypertension by Integrated Bioinformatics Analyses

2021 ◽  
Vol 12 ◽  
Author(s):  
Xue Qiu ◽  
Jinyan Lin ◽  
Bixiao Liang ◽  
Yanbing Chen ◽  
Guoqun Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Functional Enrichment ◽  
Hub Genes ◽  
Ppi Networks ◽  
Pulmonary Arterial

ObjectiveThe aim of this study is the identification of hub genes associated with idiopathic pulmonary arterial hypertension (IPAH).Materials and MethodsGSE15197 gene expression data was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by screening IPAH patients and controls. The 5,000 genes with the greatest variances were analyzed using a weighted gene co-expression network analysis (WGCNA). Modules with the strongest correlation with IPAH were chosen, followed by a functional enrichment analysis. Protein–protein interaction (PPI) networks were constructed to identify hub gene candidates using calculated degrees. Real hub genes were found from the overlap of DEGs and candidate hub genes. microRNAs (miRNAs) targeting real hub genes were found by screening miRNet 2.0. The most important IPAH miRNAs were identified.ResultsThere were 4,395 DEGs identified. WGCNA indicated that green and brown modules associated most strongly with IPAH. Functional enrichment analysis showed that green and brown module genes were mainly involved in protein digestion and absorption and proteoglycans in cancer, respectively. The top ten candidate hub genes in green and brown modules were identified, respectively. After overlapping with DEGs, 11 real hub genes were identified: EP300, MMP2, CDH2, CDK2, GNG10, ALB, SMC2, DHX15, CUL3, BTBD1, and LTN1. These genes were expressed with significant differences in IPAH versus controls, indicating a high diagnostic ability. The miRNA–gene network showed that hsa-mir-1-3p could associate with IPAH.ConclusionEP300, MMP2, CDH2, CDK2, GNG10, ALB, SMC2, DHX15, CUL3, BTBD1, and LTN1 may play essential roles in IPAH. Predicted miRNA hsa-mir-1-3p could regulate gene expression in IPAH. Such hub genes may contribute to the pathology and progression in IPAH, providing potential diagnostic and therapeutic opportunities for IPAH patients.

scholarly journals Identification of novel biomarkers involved in pulmonary arterial hypertension based on multiple-microarray analysis

2020 ◽  
Vol 40 (9) ◽  
Author(s):  
Yi Ma ◽  
Shu-Shu Chen ◽  
Yan-Yan Feng ◽  
Huan-Liang Wang
Keyword(s):  
Gene Expression ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Set Enrichment Analysis ◽  
Control Group ◽  
Hub Genes ◽  
Gene Set ◽  
Pulmonary Arterial

Abstract Pulmonary arterial hypertension (PAH) is a life-threatening chronic cardiopulmonary disorder. However, studies providing PAH-related gene expression profiles are scarce. To identify hub genes involved in PAH, we investigate two microarray data sets from gene expression omnibus (GEO). A total of 150 differentially expressed genes (DEGs) were identified by limma package. Enriched Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of DEGs mostly included mitotic nuclear division, ATPase activity, and Herpes simplex virus one infection. Ten hub genes from three significant modules were ascertained by Cytoscape (CytoHubba). Gene set enrichment analysis (GSEA) plots showed that transcription elongation factor complex was the most significantly enriched gene set positively correlated with the PAH group. At the same time, solute proton symporter activity was the most significantly enriched gene set positively correlated with the control group. Correlation analysis between hub genes suggested that SMC4, TOP2A, SMC2, KIF11, KIF23, ANLN, ARHGAP11A, SMC3, SMC6 and RAD50 may involve in the pathogenesis of PAH. Then, the miRNA-target genes regulation network was performed to unveil the underlying complex association among them. Finally, RNA extracted from monocrotaline (MCT)-induced Rat-PAH model lung artery tissues were to conduct quantitative real-time PCR (qRT-PCR) to validate these hub genes. In conclusion, our study offers new evidence for the underlying molecular mechanisms of PAH as well as attractive targets for diagnosis and treatment of PAH.

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