Integrated bioinformatic analysis reveals the underlying molecular mechanism of and potential drugs for pulmonary arterial hypertension.
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ABSTRACT:
SUBMITTER: Dong H
PROVIDER: S-EPMC8202883 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening cardiopulmonary disease lacking specific diagnostic markers and targeted therapy, and its mechanism of development remains to be elucidated. The present study aimed to explore novel diagnostic biomarkers and therapeutic targets in IPAH by integrated bioinformatics analysis. Four eligible datasets (GSE117261, GSE15197, GSE53408, GSE48149) was firstly downloaded from GEO database and subsequently integrated by Robust rank aggregation (RRA) method to screen robust differentially expressed genes (DEGs). Then functional annotation of robust DEGs was performed by GO and KEGG enrichment analysis. The protein-protein interaction (PPI) network was constructed followed by using MCODE and CytoHubba plug-in to identify hub genes. Finally, 10 hub genes were screened including ENO1, TALDO1, TXNRD1, SHMT2, IDH1, TKT, PGD, CXCL10, CXCL9, and CCL5. The GSE113439 dataset was used as a validation cohort to appraise these hub genes and TXNRD1 was selected for verification at the protein level. The experiment results confirmed that serum TXNRD1 concentration was lower in IPAH patients and the level of TXNRD1 had great predictive efficiency (AUC:0.795) as well as presents negative correlation with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR). Consistently, the expression of TXNRD1 was proved to be inhibited in animal and cellular model of PAH. In addition, GSEA analysis was performed to explore the functions of TXNRD1 and the results revealed that TXNRD1 was closely correlated with mTOR signaling pathway, MYC targets, and unfolded protein response. Finally, knockdown of TXNRD1 was shown to exacerbate proliferative disorder, migration and apoptosis resistance in PASMCs. In conclusion, our study demonstrates that TXNRD1 is a promising candidate biomarker for diagnosis of IPAH and plays an important role in PAH pathogenesis, although further research is necessary.
| S-EPMC9133447 | biostudies-literature
Project description:BackgroundPulmonary arterial hypertension (PAH) is a disease or pathophysiological syndrome which has a low survival rate with abnormally elevated pulmonary artery pressure caused by known or unknown reasons. In addition, the pathogenesis of PAH is not fully understood. Therefore, it has become an urgent matter to search for clinical molecular markers of PAH, study the pathogenesis of PAH, and contribute to the development of new science-based PAH diagnosis and targeted treatment methods.MethodsIn this study, the Gene Expression Omnibus (GEO) database was used to downloaded a microarray dataset about PAH, and the differentially expressed genes (DEGs) between PAH and normal control were screened out. Moreover, we performed the functional enrichment analyses and protein-protein interaction (PPI) network analyses of the DEGs. In addition, the prediction of miRNA and transcriptional factor (TF) of hub genes and construction miRNA-TF-hub gene network were performed. Besides, the ROC curve was used to evaluate the diagnostic value of hub genes. Finally, the potential drug targets for the 5 identified hub genes were screened out.Results69 DEGs were identified between PAH samples and normal samples. GO and KEGG pathway analyses revealed that these DEGs were mostly enriched in the inflammatory response and cytokine-cytokine receptor interaction, respectively. The miRNA-hub genes network was conducted subsequently with 131 miRNAs, 7 TFs, and 5 hub genes (CCL5, CXCL12, VCAM1, CXCR1, and SPP1) which screened out via constructing the PPI network. 17 drugs interacted with 5 hub genes were identified.ConclusionsThrough bioinformatic analysis of microarray data sets, 5 hub genes (CCL5, CXCL12, VCAM1, CXCR1, and SPP1) were identified from DEGs between control samples and PAH samples. Studies showed that the five hub genes might play an important role in the development of PAH. These 5 hub genes might be potential biomarkers for diagnosis or targets for the treatment of PAH. In addition, our work also indicated that paying more attention on studies based on these 5 hub genes might help to understand the molecular mechanism of the development of PAH.
| S-EPMC8010527 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a rare cardiovascular disease with very high mortality rate. The currently available therapeutic strategies, which improve symptoms, cannot fundamentally reverse the condition. Thus, new therapeutic strategies need to be established. Our research analyzed three microarray datasets of lung tissues from human PAH samples retrieved from the Gene Expression Omnibus (GEO) database. We combined two datasets for subsequent analyses, with the batch effects removed. In the merged dataset, 542 DEGs were identified and the key module relevant to PAH was selected using WGCNA. GO and KEGG analyses of DEGs and the key module indicated that the pre-ribosome, ribosome biogenesis, centriole, ATPase activity, helicase activity, hypertrophic cardiomyopathy, melanoma, and dilated cardiomyopathy pathways are involved in PAH. With the filtering standard (|MM| > 0.95 and |GS| > 0.90), 70 hub genes were identified. Subsequently, five candidate marker genes (CDC5L, AP3B1, ZFYVE16, DDX46, and PHAX) in the key module were found through overlapping with the top thirty genes calculated by two different methods in CytoHubb. Two of them (CDC5L and DDX46) were found to be significantly upregulated both in the merged dataset and the validating dataset in PAH patients. Meanwhile, expression of the selected genes in lung from PAH chicken measured by qRT-PCR and the ROC curve analyses further verified the potential marker genes' predictive value for PAH. In conclusion, CDC5L and DDX46 may be marker genes and potential therapeutic targets for PAH.
| S-EPMC8467453 | biostudies-literature
Project description:Diabetic cardiomyopathy (DCM) is a pathophysiological condition induced by diabetes mellitus that often causes heart failure (HF). However, their mechanistic relationships remain unclear. This study aimed to identify immune gene signatures and molecular mechanisms of DCM. Microarray data from the Gene Expression Omnibus (GEO) database from patients with DCM were subjected to weighted gene co-expression network analysis (WGCNA) identify co-expression modules. Core expression modules were intersected with the immune gene database. We analyzed and mapped protein-protein interaction (PPI) networks using the STRING database and MCODE and filtering out 17 hub genes using cytoHubba software. Finally, potential transcriptional regulatory factors and therapeutic drugs were identified and molecular docking between gene targets and small molecules was performed. We identified five potential immune biomarkers: proteosome subunit beta type-8 (PSMB8), nuclear factor kappa B1 (NFKB1), albumin (ALB), endothelin 1 (EDN1), and estrogen receptor 1 (ESR1). Their expression levels in animal models were consistent with the changes observed in the datasets. EDN1 showed significant differences in expression in both the dataset and the validation model by real-time quantitative PCR (qPCR) and Western blotting(WB). Subsequently, we confirmed that the potential transcription factors upstream of EDN1 were PRDM5 and KLF4, as its expression was positively correlated with the expression of the two transcription factors. To repurpose known therapeutic drugs, a connectivity map (CMap) database was retrieved, and nine candidate compounds were identified. Finally, molecular docking simulations of the proteins encoded by the five genes with small-molecule drugs were performed. Our data suggest that EDN1 may play a key role in the development of DCM and is a potential DCM biomarker.
| S-EPMC9421304 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a chronic cardiopulmonary syndrome with high pulmonary vascular load and eventually causing RV heart failure even death. However, the mechanism of pulmonary hypertension remains unclear. The purpose of this research is to detect the underlying key genes and potential mechanism of PAH using several bioinformatic methods. The microarrays GSE22356, GSE131793 and GSE168905 were acquired from the GEO. Subsequently, a host of bioinformatics techniques such as DAVID, STRING, R language and Cytoscape were utilized to investigate DEGs between PAH and healthy controls and conduct GO annotation, KEGG enrichment analysis and PPI network construction etc. Additionally, we predicted the transcription factors regulating DEGs through iRegulon plugin of Cytoscape and CIBERSORT was used to conduct immune infiltration analysis. One thousand two hundred and seventy-seven DEGs (403 up-regulated and 874 down-regulated) were identified from peripheral blood samples of 32 PAH patients and 29 controls, among which SLC4A1, AHSP, ALAS2, CA1, HBD, SNCA, HBM, SELENBP1, SERPINE1 and ITGA2B were detected as hub genes. The functional enrichment changes of DEGs were mainly enriched in protein binding, extracellular exosome, extracellular space, extracellular region and integral component of plasma membrane. The hub genes are chiefly enriched at extracellular exosome, hemoglobin complex, blood microparticle, oxygen transporter activity. Among TF-DEGs network, 42 target DEGs and 6 TFs were predicted with an NES > 4 (TEAD4, TGIF2LY, GATA5, GATA1, GATA2, FOS). Immune infiltration analysis showed that monocytes occupied the largest proportion of immune cells. The trend analysis results of infiltration immune cells illustrated that PAH patients had higher infiltration of NK cell activation, monocyte, T cell CD4 memory activation, and mast cell than healthy controls and lower infiltration of T cell CD4 naive. We detected SLC4A1, AHSP, ALAS2, CA1, HBD, SNCA, HBM, SELENBP1, SERPINE1 and ITGA2B as the most significant markers of PAH. The PAH patients had higher infiltration of NK cell activation, monocyte, T cell CD4 memory activation, and mast cell than healthy controls and lower infiltration of T cell CD4 naive. These identified genes and these immune cells probably have precise regulatory relationships in the development of PAH.
| S-EPMC9203517 | biostudies-literature
Project description:Pulmonary arterial hypertension is a chronic, progressive disorder of the pulmonary vasculature with associated pulmonary and cardiac remodeling. PAH was a uniformly fatal disease until the late 1970s, but with the advent of targeted therapies, the life expectancy of patients with PAH has now considerably improved. Despite these advances, PAH inevitably remains a progressive disease with significant morbidity and mortality. Thus, there is still an unmet need for the development of new drugs and other interventional therapies for the treatment of PAH. One shortcoming of currently approved vasodilator therapies is that they do not target or reverse the underlying pathogenesis of the disease process itself. A large body of evidence has evolved in the past two decades clarifying the role of genetics, dysregulation of growth factors, inflammatory pathways, mitochondrial dysfunction, DNA damage, sex hormones, neurohormonal pathways, and iron deficiency in the pathogenesis of PAH. This review focuses on newer targets and drugs that modify these pathways as well as novel interventional therapies in PAH.
| S-EPMC10058689 | biostudies-literature
Project description:IntroductionIdiopathic 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.MethodsMicroarray 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.Results30 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.ConclusionOur 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.
| S-EPMC7355352 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-? pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.
| S-EPMC5897357 | biostudies-literature
Project description:Microarray analysis of peripheral blood mononuclear (PBMC) cells in pulmonary arterial hypertension. Keywords = mononuclear cells Keywords = gene microarray Keywords = pulmonary arterial hypertension Keywords = Herpesvirus Keywords = biomarker Keywords: other
2003-11-15 | GSE703 | GEO
Project description:Idiopathic pulmonary arterial hypertension (IPAH) is a rare vascular disease with a poor prognosis, and the mechanism of its development remains unclear. Further molecular pathology studies may contribute to a comprehensive understanding of IPAH and provide new insights into diagnostic markers and potential therapeutic targets. Iron deficiency has been reported in 43-63% of patients with IPAH and is associated with reduced exercise capacity and higher mortality, suggesting that dysregulated iron metabolism may play an unrecognized role in influencing the development of IPAH. In this study, we explored the regulatory mechanisms of iron metabolism in IPAH by bioinformatic analysis. The molecular function of iron metabolism-related genes (IMRGs) is mainly enriched in active transmembrane transporter activity, and they mainly affect the biological process of response to oxidative stress. Ferroptosis and fluid shear stress and atherosclerosis pathways may be the critical pathways regulating iron metabolism in IPAH. We further identified 7 key genes (BCL2, GCLM, MSMO1, SLC7A11, SRXN1, TSPAN5, and TXNRD1) and 5 of the key genes (BCL2, MSMO1, SLC7A11, TSPAN5, and TXNRD1) as target genes may be regulated by 6 dysregulated miRNAs (miR-483-5p, miR-27a-3p, miR-27b-3p, miR-26b-5p, miR-199a-5p, and miR-23b-3p) in IPAH. In addition, we predicted potential IPAH drugs-celastrol and cinnamaldehyde-that target iron metabolism based on our results. These results provide insights for further definition of the role of dysregulated iron metabolism in IPAH and contribute to a deeper understanding of the molecular mechanisms and potential therapeutic targets of IPAH.
| S-EPMC8556088 | biostudies-literature