Screening of key biomarkers and immune infiltration in Pulmonary Arterial Hypertension via integrated bioinformatics analysis

Zeng, Yu; Li, Nanhong; Zheng, Zhenzhen; Chen, Riken; Liu, Wang; Cheng, Junfen; Zhu, Jiang; Zeng, Mingqing; Peng, Min; Hong, Cheng

doi:10.1080/21655979.2021.1936816

Cited by 15 publications

(11 citation statements)

References 64 publications

(61 reference statements)

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“…Furthermore, it has been found that the pathological process of PAH can lead to an increased ubiquitin-proteasome system- (UPS-) mediated muscle protein degradation and mitochondrial abnormalities, which in turn cause extensive abnormalities in skeletal and respiratory muscles of PAH patients, ultimately causing PAH-related restriction of motor function [ 47 ]. Previous studies have reported that NF- κ B can regulate gene expression and then be involved in many biological processes, such as inflammatory factor production, cell proliferation, effector cell survival, and differentiation, and that the NF- κ B signaling pathway is aberrantly activated in PAH models [ 48 , 49 ]. The new anesthetic sevoflurane can downregulate the levels of p-I κ B, p-P65, and P65 to inhibit NF- κ B signaling pathway activation in PAH rat models, thereby reducing lung fibrosis and ultimately preventing PAH [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Identifying Potential Mitochondrial Proteome Signatures Associated with the Pathogenesis of Pulmonary Arterial Hypertension in the Rat Model

Wang

Uddin

et al. 2022

Oxidative Medicine and Cellular Longevity

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Pulmonary arterial hypertension (PAH) is a severe and progressive disease that affects the heart and lungs and a global health concern that impacts individuals and society. Studies have reported that some proteins related to mitochondrial metabolic functions could play an essential role in the pathogenesis of PAH, and their specific expression and biological function are still unclear. We successfully constructed a monocrotaline- (MCT-) induced PAH rat model in the present research. Then, the label-free quantification proteomic technique was used to determine mitochondrial proteins between the PAH group ( n = 6 ) and the normal group ( n = 6 ). Besides, we identified 1346 mitochondrial differentially expressed proteins (DEPs) between these two groups. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the mainly mitochondrial DEPs’ biological functions and the signal pathways. Based on the protein-protein interaction (PPI) network construction and functional enrichment, we screened 19 upregulated mitochondrial genes (Psmd1, Psmc4, Psmd13, Psmc2, etc.) and 123 downregulated mitochondrial genes (Uqcrfs1, Uqcrc1, Atp5c1, Atp5a1, Uqcrc2, etc.) in rats with PAH. Furthermore, in an independent cohort dataset and experiments with rat lung tissue using qPCR, validation results consistently showed that 6 upregulated mitochondrial genes (Psmd2, Psmc4, Psmc3, Psmc5, Psmd13, and Psmc2) and 3 downregulated mitochondrial genes (Lipe, Cat, and Prkce) were significantly differentially expressed in the lung tissue of PAH rats. Using the RNAInter database, we predict potential miRNA target hub mitochondrial genes at the transcriptome level. We also identified bortezomib and carfilzomib as the potential drugs for treatment in PAH. Finally, this study provides us with a new perspective on critical biomarkers and treatment strategies in PAH.

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Section: Discussionmentioning

confidence: 99%

Identifying Potential Mitochondrial Proteome Signatures Associated with the Pathogenesis of Pulmonary Arterial Hypertension in the Rat Model

Wang

Uddin

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Most of these studies apply machine learning methods to simulate the progression of malignancy and find significant characteristics that are then used in a categorization scheme. According to the results of our study and those of other researchers [50][51][52][53][54][55][56], this was the first study in which analytical methods for identifying PAH biomarkers use many machine learning approaches, including RF, Lasso, SVM-RFE, and WGCNA. Akter et al [57] suggest that merging different machine learning algorithms may boost prediction performance and construct highly accurate diagnostic models.…”

Section: Discussionmentioning

confidence: 63%

FAM171B as a Novel Biomarker Mediates Tissue Immune Microenvironment in Pulmonary Arterial Hypertension

Luo

Yan

et al. 2022

Mediators of Inflammation

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The purpose of this study was to uncover potential diagnostic indicators of pulmonary arterial hypertension (PAH), evaluate the function of immune cells in the pathogenesis of the disease, and find innovative treatment targets and medicines with the potential to enhance prognosis. Gene Expression Omnibus was utilized to acquire the PAH datasets. We recognized differentially expressed genes (DEGs) and investigated their functions utilizing R software. Weighted gene coexpression network analysis, least absolute shrinkage and selection operators, and support vector machines were used to identify biomarkers. The extent of immune cell infiltration in the normal and PAH tissues was determined using CIBERSORT. Additionally, the association between diagnostic markers and immune cells was analyzed. In this study, 258DEGs were used to analyze the disease ontology. Most DEGs were linked with atherosclerosis, arteriosclerotic cardiovascular disease, and lung disease, including obstructive lung disease. Gene set enrichment analysis revealed that compared to normal samples, results from PAH patients were mostly associated with ECM-receptor interaction, arrhythmogenic right ventricular cardiomyopathy, the Wnt signaling pathway, and focal adhesion. FAM171B was identified as a biomarker for PAH ( area under the curve = 0.873 ). The mechanism underlying PAH may be mediated by nave CD4 T cells, resting memory CD4 T cells, resting NK cells, monocytes, activated dendritic cells, resting mast cells, and neutrophils, according to an investigation of immune cell infiltration. FAM171B expression was also associated with resting mast cells, monocytes, and CD8 T cells. The results suggest that PAH may be closely related to FAM171B with high diagnostic performance and associated with immune cell infiltration, suggesting that FAM171B may promote the progression of PAH by stimulating immune infiltration and immune response. This study provides valuable insights into the pathogenesis and treatment of PAH.

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“…From a broad perspective, the development of PDS for clinical application is of great significance. Previous studies have examined key genes by DEG analysis between PAH lung specimens and normal lung specimens solely based on the public database in the GEO (27)(28)(29). The presence of heterogeneity of the disease and confounding factors reduces the sensitivity and specificity of DEGs as biomarkers for PAH.…”

Section: Discussionmentioning

confidence: 99%

Construction of a diagnostic signature and immune landscape of pulmonary arterial hypertension

Duo

Han

Zhang

et al. 2022

Front. Cardiovasc. Med.

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BackgroundMolecular biomarkers are widely used for disease diagnosis and exploration of pathogenesis. Pulmonary arterial hypertension (PAH) is a rapidly progressive cardiopulmonary disease with delayed diagnosis. Studies were limited regarding molecular biomarkers correlated with PAH from a broad perspective.MethodsTwo independent microarray cohorts comprising 73 PAH samples and 36 normal samples were enrolled in this study. The weighted gene co-expression network analysis (WGCNA) was performed to identify the key modules associated with PAH. The LASSO algorithm was employed to fit a diagnostic model. The latent biology mechanisms and immune landscape were further revealed via bioinformatics tools.ResultsThe WGCNA approach ultimately identified two key modules significantly associated with PAH. For genes within the two models, differential expression analysis between PAH and normal samples further determined nine key genes. With the expression profiles of these nine genes, we initially developed a PAH diagnostic signature (PDS) consisting of LRRN4, PI15, BICC1, PDE1A, TSHZ2, HMCN1, COL14A1, CCDC80, and ABCB1 in GSE117261 and then validated this signature in GSE113439. The ROC analysis demonstrated outstanding AUCs with 0.948 and 0.945 in two cohorts, respectively. Besides, patients with high PDS scores enriched plenty of Th17 cells and neutrophils, while patients with low PDS scores were dramatically related to mast cells and B cells.ConclusionOur study established a robust and promising signature PDS for diagnosing PAH, with key genes, novel pathways, and immune landscape offering new perspectives for exploring the molecular mechanisms and potential therapeutic targets of PAH.

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Screening of key biomarkers and immune infiltration in Pulmonary Arterial Hypertension via integrated bioinformatics analysis

Cited by 15 publications

References 64 publications

Identifying Potential Mitochondrial Proteome Signatures Associated with the Pathogenesis of Pulmonary Arterial Hypertension in the Rat Model

Identifying Potential Mitochondrial Proteome Signatures Associated with the Pathogenesis of Pulmonary Arterial Hypertension in the Rat Model

FAM171B as a Novel Biomarker Mediates Tissue Immune Microenvironment in Pulmonary Arterial Hypertension

Construction of a diagnostic signature and immune landscape of pulmonary arterial hypertension

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