Single-cell RNA-sequencing and microarray analyses to explore the pathological mechanisms of chronic thromboembolic pulmonary hypertension

Miao, Ran; Dong, Xingbei; Gong, Juanni; Li, Yidan; Guo, Xiaojuan; Wang, Jianfeng; Huang, Qiang; Wang, Ying; Li, Jifeng; Yang, Suqiao; Kuang, Tuguang; Liu, Min; Wan, Jun; Zhai, Zhenguo; Zhong, Jiuchang; Yang, Yuanhua

doi:10.3389/fcvm.2022.900353

Cited by 3 publications

(4 citation statements)

References 42 publications

(49 reference statements)

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“…The results showed that the activity of ITGB2 signaling pathway was increased in SLE and pSS patients, and the ITGB2 signaling pathway was most enriched from monocytes to CD4 T cells and CD8 effector T cells ( Figures 10C, D ). The ITGB2, ICAM1, ICAM2, CD226 and ITGAL expression levels related to ITGB2 signaling pathway were verified both in scRNA-seq and microarray datasets between disease conditions and healthy controls ( 51 , 52 ) ( Supplementary Figure 7 ). The results demonstrated that ITGB2 signaling pathway related genes were upregulated both in SLE and pSS patients, though some were not statistically significantly so.…”

Section: Resultsmentioning

confidence: 75%

Exploring the shared molecular mechanisms between systemic lupus erythematosus and primary Sjögren’s syndrome based on integrated bioinformatics and single-cell RNA-seq analysis

Cui,

Zhang,

Wang

et al. 2023

Front. Immunol.

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BackgroundSystemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) are common systemic autoimmune diseases that share a wide range of clinical manifestations and serological features. This study investigates genes, signaling pathways, and transcription factors (TFs) shared between SLE and pSS.MethodsGene expression profiles of SLE and pSS were obtained from the Gene Expression Omnibus (GEO). Weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis were conducted to identify shared genes related to SLE and pSS. Overlapping genes were then subject to Gene Ontology (GO) and protein-protein interaction (PPI) network analyses. Cytoscape plugins cytoHubba and iRegulon were subsequently used to screen shared hub genes and predict TFs. In addition, gene set variation analysis (GSVA) and CIBERSORTx were used to calculate the correlations between hub genes and immune cells as well as related pathways. To confirm these results, hub genes and TFs were verified in microarray and single-cell RNA sequencing (scRNA-seq) datasets.ResultsFollowing WGCNA and limma analysis, 152 shared genes were identified. These genes were involved in interferon (IFN) response and cytokine-mediated signaling pathway. Moreover, we screened six shared genes, namely IFI44L, ISG15, IFIT1, USP18, RSAD2 and ITGB2, out of which three genes, namely IFI44L, ISG15 and ITGB2 were found to be highly expressed in both microarray and scRNA-seq datasets. IFN response and ITGB2 signaling pathway were identified as potentially relevant pathways. In addition, STAT1 and IRF7 were identified as common TFs in both diseases.ConclusionThis study revealed IFI44L, ISG15 and ITGB2 as the shared genes and identified STAT1 and IRF7 as the common TFs of SLE and pSS. Notably, the IFN response and ITGB2 signaling pathway played vital roles in both diseases. Our study revealed common pathogenetic characteristics of SLE and pSS. The particular roles of these pivotal genes and mutually overlapping pathways may provide a basis for further mechanistic research.

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Section: Resultsmentioning

confidence: 75%

Exploring the shared molecular mechanisms between systemic lupus erythematosus and primary Sjögren’s syndrome based on integrated bioinformatics and single-cell RNA-seq analysis

Cui,

Zhang,

Wang

et al. 2023

Front. Immunol.

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“…Of significance is the downregulation of let-7d microRNA, which may repress the proliferation of PASMCs by upregulating p21, arresting the cell cycle at the G1 phase, and therefore possibly affecting vascular remodeling in CTEPH [108]. Eleven cell types are possibly affected in CTEPH with differentially expressed microRNAs and circular RNAs [109]. Miao et al found that tumor protein p53, ICAM1, amyloid-β precursor protein (APP), integrin subunit β2 (ITGB2), and zyxin have the highest degree of connectivity in the protein-protein interaction network of different cell types in CTEPH [109].…”

Section: Genetic Backgroundmentioning

confidence: 99%

“…Eleven cell types are possibly affected in CTEPH with differentially expressed microRNAs and circular RNAs [109]. Miao et al found that tumor protein p53, ICAM1, amyloid-β precursor protein (APP), integrin subunit β2 (ITGB2), and zyxin have the highest degree of connectivity in the protein-protein interaction network of different cell types in CTEPH [109]. This shows that CTEPH involves multipathogenic pathways; however, which one is predominant, how they interact, and how they differentially affect individual patients is not entirely clear.…”

Section: Genetic Backgroundmentioning

confidence: 99%

Chronic Thromboembolic Pulmonary Hypertension: A Review of the Multifaceted Pathobiology

Ghani,

Pepke-Zaba

2023

Biomedicines

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Chronic thromboembolic pulmonary disease results from the incomplete resolution of thrombi, leading to fibrotic obstructions. These vascular obstructions and additional microvasculopathy may lead to chronic thromboembolic pulmonary hypertension (CTEPH) with increased pulmonary arterial pressure and pulmonary vascular resistance, which, if left untreated, can lead to right heart failure and death. The pathobiology of CTEPH has been challenging to unravel due to its rarity, possible interference of results with anticoagulation, difficulty in selecting the most relevant study time point in relation to presentation with acute pulmonary embolism (PE), and lack of animal models. In this article, we review the most relevant multifaceted cross-talking pathogenic mechanisms and advances in understanding the pathobiology in CTEPH, as well as its challenges and future direction. There appears to be a genetic background affecting the relevant pathological pathways. This includes genetic associations with dysfibrinogenemia resulting in fibrinolysis resistance, defective angiogenesis affecting thrombus resolution, and inflammatory mediators driving chronic inflammation in CTEPH. However, these are not necessarily specific to CTEPH and some of the pathways are also described in acute PE or deep vein thrombosis. In addition, there is a complex interplay between angiogenic and inflammatory mediators driving thrombus non-resolution, endothelial dysfunction, and vascular remodeling. Furthermore, there are data to suggest that infection, the microbiome, circulating microparticles, and the plasma metabolome are contributing to the pathobiology of CTEPH.

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“…Moreover, BPA treatment has been demonstrated to decrease interleukin (IL)-6 and C-reactive protein levels in CTEPH patients, indicating its potential to improve systemic inflammation (5). Although transcriptome sequencing and bioinformatics analysis have been used to investigate the pathogenesis of CTEPH (6), proteomic studies assessing the therapeutic efficacy of BPA are lacking.…”

Section: Introductionmentioning

confidence: 99%

Serum ASGR2 level: an efficacy biomarker for balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension

Xu,

Wang,

Zhao

et al. 2024

Front. Immunol.

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BackgroundThis study aimed to employ plasma proteomics to investigate the molecular changes, pathway alterations, and potential novel biochemical markers associated with balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH).MethodsPre- and post-BPA plasma samples from five CTEPH patients in the PRACTICE study were analyzed to identify differentially expressed proteins. Proteomic and bioinformatics analyses were conducted, and the identified proteins were further validated using ELISA assays in a separate cohort of the same study. Correlation and multivariate regression analyses were performed to investigate the associations between these differentially expressed proteins and clinical parameters.ResultsSignificantly higher serum levels of asialoglycoprotein receptor 2 (ASGR2) were detected in 5 CTEPH patients compared to those in healthy individuals but decreased significantly after successful BPA procedures. The decrease in serum levels of ASGR2 after the completion of BPA procedures was further validated in a separate cohort of 48 patients with CTEPH [0.70 (0.51, 1.11) ng/mL vs. 0.38 (0.27, 0.59) ng/mL, P < 0.001]. Significant associations were found between the pre-BPA ASGR2 level and clinical parameters, including neutrophil percentage (R = 0.285, P < 0.05), platelet (PLT) count (R = 0.386, P < 0.05), and high-density lipoprotein cholesterol (HDL-C) before BPA (R = -0.285, P < 0.05). Significant associations were detected between post-BPA serum ASGR2 levels and lymphocyte percentage (LYM%) (R = 0.306, P < 0.05), neutrophil-to-lymphocyte ratio (R = -0.294, P < 0.05), and pulmonary vascular resistance after BPA (R = -0.35, P < 0.05). Multivariate stepwise regression analysis revealed that pre-BPA ASGR2 levels were associated with HDL-C and PLT count (both P < 0.001), while post-BPA ASGR2 levels were associated with LYM% (P < 0.05).ConclusionSerum levels of ASGR2 may be a biomarker for the effectiveness of BPA treatment in CTEPH patients. The pre-BPA serum level of ASGR2 in CTEPH patients was associated with HDL-C and the PLT count. The post-BPA serum level of ASGR2 was correlated with the LYM%, which may reflect aspects of immune and inflammatory status.

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Single-cell RNA-sequencing and microarray analyses to explore the pathological mechanisms of chronic thromboembolic pulmonary hypertension

Cited by 3 publications

References 42 publications

Exploring the shared molecular mechanisms between systemic lupus erythematosus and primary Sjögren’s syndrome based on integrated bioinformatics and single-cell RNA-seq analysis

Exploring the shared molecular mechanisms between systemic lupus erythematosus and primary Sjögren’s syndrome based on integrated bioinformatics and single-cell RNA-seq analysis

Chronic Thromboembolic Pulmonary Hypertension: A Review of the Multifaceted Pathobiology

Serum ASGR2 level: an efficacy biomarker for balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension

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