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.

Gene expression profile in flow-associated pulmonary arterial hypertension with neointimal lesions

2010 ◽  
Vol 298 (4) ◽  
pp. L483-L491 ◽  
Author(s):  
Mirjam E. van Albada ◽  
Beatrijs Bartelds ◽  
Hans Wijnberg ◽  
Saffloer Mohaupt ◽  
Michael G. Dickinson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blood Flow ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Blood Flow ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Response To Therapy ◽  
High Morbidity ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a pulmonary angioproliferative disease with high morbidity and mortality, characterized by a typical pattern of pulmonary vascular remodeling including neointimal lesions. In congenital heart disease, increased pulmonary blood flow has appeared to be a key mediator in the development of these characteristic lesions, but the molecular mechanisms underlying the pulmonary vascular lesions are largely unknown. We employed a rat model of flow-associated PAH, which induced specific pulmonary neointimal lesions. We identified gene expression profiles in rats specifically related to the addition of increased pulmonary blood flow to monocrotaline and the associated occurrence of neointimal lesions. Increased pulmonary blood flow induced the expression of the transcription factors activating transcription factor-3 (ATF3) and early growth response factor-1 (EGR-1), for which presence was confirmed in neointimal lesions. Monocrotaline alone induced increased numbers of activated mast cells and their products. We further identified molecular pathways that may be involved in treatment with the prostacyclin analog iloprost, a vasoactive compound with clinically beneficial effects in patients with PAH, which were similar to pathways described in samples from patient studies. These pathways, associated with the development of angioproliferative lesions as well as with the response to therapy in PAH, may provide new therapeutic targets.

scholarly journals Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease

2018 ◽  
Vol 3 (3) ◽  
pp. 242-248 ◽  
Author(s):  
Matthew Moll ◽  
Romy B Christmann ◽  
Yuqing Zhang ◽  
Michael L Whitfield ◽  
Yu Mei Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Interstitial Lung Disease ◽  
Arterial Hypertension ◽  
Lung Disease ◽  
Expression Profiles ◽  
Area Under The Curve ◽  
Gene Expression Profiles ◽  
Pulmonary Arterial

Objective: Pulmonary arterial hypertension and interstitial lung disease are major causes of mortality in systemic sclerosis. We used a previously identified microarray biomarker to determine whether systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease patients demonstrate distinct gene expression profiles. Methods: Peripheral blood mononuclear cells were collected from healthy controls ( n = 10), systemic sclerosis patients without pulmonary hypertension (systemic sclerosis-no pulmonary arterial hypertension, n = 39), and systemic sclerosis-pulmonary arterial hypertension patients ( n = 21; mean pulmonary arterial pressure ≥25, pulmonary capillary wedge pressure ≤15, and pulmonary vascular resistance ≥3 Wood units) diagnosed by right heart catheterization. Systemic sclerosis-interstitial lung disease patients were defined as those with evidence of fibrosis on chest computed tomography and significant restriction (forced vital capacity <70% predicted, n = 11). Systemic sclerosis-pulmonary arterial hypertension biomarker included 69 genes selected by unbiased statistical screening of three publicly available microarray studies. RNA levels were measured by NanoString Technologies. Gene expression levels that were significantly correlated with pulmonary arterial hypertension (multiple statistical measures) were chosen as inputs into a forward selection logistic regression model. Results: When interstitial lung disease patients were included ( n = 64), four genes (S100P, CD8B1, CCL2, and TIMP1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.83). Without interstitial lung disease patients ( n = 53), two genes (THBS1 and CD8B1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.80). When examining systemic sclerosis patients with borderline elevated pulmonary pressures (mean pulmonary arterial pressure = 21–24 mmHg), gene expression changes closely resembled the systemic sclerosis-pulmonary arterial hypertension group, except for THBS1. Conclusion: Systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease have similar but distinct gene expression profiles. Many gene expression changes occur early in the disease course, potentially allowing early detection. THBS1 appears to be an important mediator in the development of pulmonary arterial hypertension-predominant phenotype. Further prospective investigation is warranted.

scholarly journals Profiling and Molecular Mechanism Analysis of Long Non-Coding RNAs and mRNAs in Pulmonary Arterial Hypertension Rat Models

2021 ◽  
Vol 12 ◽  
Author(s):  
Shiqiang Hou ◽  
Dandan Chen ◽  
Jie Liu ◽  
Shasha Chen ◽  
Xiaochun Zhang ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
Expression Profiles ◽  
Macrophage Polarization ◽  
Mechanism Analysis ◽  
Rat Models ◽  
Pulmonary Arterial ◽  
Non Coding Rnas

Pulmonary arterial hypertension (PAH) is an immune-mediated disease with poor prognosis and associated with various inflammatory immune diseases. In fact, its pathogenesis is far from clear. Although long non-coding RNAs (lncRNAs) have been implicated in PAH, the molecular mechanisms remain largely unknown. For the first time, in lungs of monocrotaline-induced PAH rat models, we simultaneously detected the expression profiles of lncRNAs and mRNAs by high-throughput sequencing, and explored their roles with bioinformatics analysis and cell assay to discover more potential pathogenesis about PAH. Our data identified that a total of 559 lncRNAs and 691 mRNAs were differentially expressed in lungs during the pathogenesis of PAH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated that these dysregulated lncRNAs and mRNAs participated in important biological processes and pathways of PAH, among which inflammatory and immune responses represented the chief enriched pathway. The lncRNA-mRNA co-expression network was developed to uncover the hidden interactions between lncRNAs and mRNAs. Further, the expression levels of lncRNAs (NONRATT018084.2, NONRATT009275.2, NONRATT007865.2, and NONRATT026300.2) and mRNAs (LGALS3, PDGFC, SERPINA1, and NFIL3) were confirmed using quantitative real-time PCR. In the end, lncRNA NONRATT009275.2 could facilitate macrophage polarization to M2 type and be involved in inflammatory immune response. In conclusion, this study provided candidate drug targets and potential roles on lncRNAs in the pathogenesis of PAH, and several key regulatory genes were identified, which laid the initial foundation for further mechanism study in PAH.

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 Candidate Genes Identified in Systemic Sclerosis-Related Pulmonary Arterial Hypertension Were Associated with Immunity, Inflammation, and Cytokines

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Zhixiao Xu ◽  
Jiaxing Ruan ◽  
Lingyun Pan ◽  
Chengshui Chen
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Candidate Genes ◽  
Coexpression Network ◽  
Gene Coexpression Network ◽  
Hub Genes ◽  
Gene Coexpression ◽  
Pulmonary Arterial

Background. Pulmonary complications of systemic sclerosis (SSc), including pulmonary arterial hypertension (PAH), are the leading causes of patient death. However, the precise molecular mechanisms of its etiology are unclear. This study’s objective was to identify the candidate genes involved in the progression of SSc-PAH and investigate the genes' function. Methods. The gene expression profiles of GSE33463 were obtained from the Gene Expression Omnibus (GEO) database. A free-scale gene coexpression network was constructed using the weighted gene coexpression network analysis (WGCNA) to explore the association between gene sets and clinical features and identify candidate biomarkers. Then, gene ontology analysis was performed. A second dataset was used, GSE19617, to validate the hub genes. The verified hub genes’ potential function was further explored using gene set enrichment analysis (GSEA). Results. Through average link-level clustering, a total of seven modules were classified. A total of 938 hub genes were identified in the key module, and the key module’s function mainly enriched was related to chemokine activities. Subsequently, four candidate genes, BTG3, CCR2, RAB10, and TMEM60, were filtered. The expression levels of these four hub genes were consistent in the GSE19617 and GSE33463 datasets. We plotted the ROC curve of the hub genes (all AUC > 0.70 ). Furthermore, the results of the GSEA for hub genes were correlated with complement and inflammatory responses. Conclusions. The hub genes (BTG3, CCR2, RAB10, and TMEM60) performed well in distinguishing the SSc-PAH patients from controls, and some biological functions, related to immunity, inflammation, and cytokines, might pave the way for follow-up studies on the diagnosis and treatment of SSc-PAH.

scholarly journals Long non-coding RNA expression profiling in the lungs of pulmonary arterial hypertension rats with acute inflammation

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401987939
Author(s):  
Yue Yang ◽  
Yanan Cao ◽  
Gang Qin ◽  
Lu Wang ◽  
Qian Li ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Acute Inflammation ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Control Group ◽  
Messenger Rnas ◽  
Bioinformatics Analyses ◽  
Qrt Pcr ◽  
Pulmonary Arterial

Background We performed RNA-sequencing to investigate the changes and expression profiles in long non-coding RNAs (lncRNAs) and their potential functional roles in the lungs of pulmonary arterial hypertension rats responding to acute inflammation. Methods To establish a pulmonary arterial hypertension rat model, monocrotaline was injected intraperitoneally and lipopolysaccharide was given to induce acute inflammation. Selected lncRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatics analyses were carried out to predict the potential biological roles of key lncRNAs. Results Twenty-eight lncRNAs and seven mRNAs with elevated expression and 202 lncRNAs and 36 mRNAs with decreased expression were found in the lung tissues of lipopolysaccharide-treated pulmonary arterial hypertension rats compared with control group. The qRT-PCR validation results were consistent with the bioinformatics analysis. Gene ontology analyses showed that the mRNAs and lncRNAs were differentially expressed in different pathways regarding biological process, cellular components, and molecular function. The functions of differentially expressed messenger RNAs (DEmRNAs) and DElncRNAs were indicated by Kyoto Encyclopedia of Genes and Genomes enrichment. Conclusion The DEmRNAs co-expressed with DElncRNAs were obviously enriched in inflammation. DElncRNAs and DEmRNAs in the lungs of pulmonary arterial hypertension rats changed with acute inflammation may provide new insights into the pathogenesis of pulmonary arterial hypertension.

scholarly journals Preventive training interferes with mRNA-encoding myosin 7 and collagen I expression during pulmonary arterial hypertension

2020 ◽  
Author(s):  
Thaoan Bruno Mariano ◽  
Anthony César de Souza Castilho ◽  
Ana Karenina Dias de Almeida Sabela ◽  
André Casanova de Oliveira ◽  
Sarah Santiloni Cury ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Cardiac Dysfunction ◽  
Positive Impact ◽  
Control Group ◽  
Pulmonary Arterial ◽  
The Impact

AbstractTo gain insight on the impact of preventive exercise during pulmonary arterial hypertension (PAH), we evaluated the gene expression of myosins and gene-encoding proteins associated with the extracellular matrix remodeling of right hypertrophied ventricles. We used 32 male Wistar rats, separated in four groups: Sedentary Control (S; n=8); Control with Training (T; n=8); Sedentary with Pulmonary Arterial Hypertension (SPAH; n=8); and Pulmonary Arterial Hypertension with Training (TPAH; n=8). The rats trained for thirteen weeks on a treadmill. They had two weeks of adaptation training. The PAH was induced by application of monocrotaline 60 mg/kg. Consequential right ventricular dysfunction was observed after the 10th week of training. Rats in the control group received saline application. At the end of the 13th week, echocardiography analysis confirmed cardiac dysfunction. Collagen content and organization was assessed through picrosirius red staining and fractal dimension (FD) analysis, respectively. Transcript abundance was estimated through reverse transcription-quantitative PCR (RT-qPCR). Cardiac dysfunction was confirmed by the reduction in maximum pulmonary artery velocity and pulmonary artery acceleration time. Through histomorphometric assessment, we found no differences in the interstitial collagen FD between groups. Regarding gene expression, myh7 gene expression was upregulated in the TPAH group. However, this did not occur with the S group. PAH also increased the mRNA abundance of col1a1 in the SPAH and TPAH groups. Moreover, the TPAH group showed a higher abundance of this gene when compared to the S group. With these findings, we concluded that preventive exercise had a positive impact on compensated hypertrophy during pulmonary hypertension. This can be explained in part by the modulation of the extracellular matrix and myosin gene expression in trained rats.

scholarly journals Identification of ferroptosis-associated genes exhibiting altered expression in pulmonary arterial hypertension

2021 ◽  
Vol 18 (6) ◽  
pp. 7619-7630
Author(s):  
Fan Zhang ◽  
◽  
Hongtao Liu ◽  
Keyword(s):  
Cell Death ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Pathway Enrichment Analysis ◽  
Altered Expression ◽  
Network Analyses ◽  
Pulmonary Arterial

<abstract> <p>Pulmonary arterial hypertension (PAH) is a life-threatening illness and ferroptosis is an iron-dependent form of regulated cell death, driven by the accumulation of lipid peroxides to levels that are sufficient to trigger cell death. However, only few studies have examined PAH-associated ferroptosis. In the present study, lung samples mRNA expression profiles (derived from 15 patients with PAH and 11 normal controls) were downloaded from a public database, and 514 differentially expressed genes (DEGs) were identified using the Wilcoxon rank-sum test and weighted gene correlation network analyses. These DEGs were screened for ferroptosis-associated genes using the FerrDb database: eight ferroptosis-associated genes were identified. Finally, the construction of gene-microRNA (miRNA) and gene-transcription factor (TF) networks, in conjunction with gene ontology and biological pathway enrichment analysis, were used to inform hypotheses regarding the molecular mechanisms underlying PAH-associated ferroptosis. Ferroptosis-associated genes were largely involved in oxidative stress responses and could be regulated by several identified miRNAs and TFs. This suggests the existence of modulatable pathways that are potentially involved in PAH-associated ferroptosis. Our findings provide novel directions for targeted therapy of PAH in regard to ferroptosis. These findings may ultimately help improve the therapeutic outcomes of PAH.</p> </abstract>

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