Targeting IL-17 attenuates hypoxia-induced pulmonary hypertension through downregulation of β-catenin

Wang, Lei; Liu, Jie; Wang, Wang; Qi, Xianmei; Wang, Ying; Tian, Bo; Dai, Huaping; Wang, Jing; Ning, Wen; Yang, Ting; Wang, Chen

doi:10.1136/thoraxjnl-2018-211846

Cited by 38 publications

(38 citation statements)

References 51 publications

(26 reference statements)

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“…HPAH and CTEPH are two common types of PH (1). PASMCs in HPAH and CTEPH exhibit proliferation and migration phenotypes similar to those of cancer cells (25,26). In the present study, EZH2 expression levels were increased in both hypoxia-induced and patient-derived PASMCs, which is consistent with a previous study in a hypoxia-induced PAH mouse model (11).…”

Section: Discussionsupporting

confidence: 92%

Effect of EZH2 on pulmonary artery smooth muscle cell migration in pulmonary hypertension

Wang

Huang²,

Dong

et al. 2020

Mol Med Rep

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Pulmonary hypertension (PH) is a life-threatening disease that often involves vascular remodeling. Although pulmonary arterial smooth muscle cells (PASMCs) are the primary participants in vascular remodeling, their biological role is not entirely clear. The present study analyzed the role of enhancer of zeste homolog 2 (EZH2) in vascular remodeling of PH by investigating the behavior of PASMCs. The expression levels of EZH2 in PASMCs in chronic thromboembolic pulmonary hypertension (CTEPH), a type of PH, were detected. The role of EZH2 in PASMC migration was investigated by wound-healing assay following overexpression and knockdown. Functional enrichment analysis of the whole-genome expression profiles of PASMCs with EZH2 overexpression was performed using an mRNA Human Gene Expression Microarray. Quantitative (q)PCR was performed to confirm the results of the microarray. EZH2 expression levels increased in CTEPH cell models. The overexpression of EZH2 enhanced PASMC migration compared with control conditions. Functional enrichment analysis of the differentially expressed genes following EZH2 overexpression indicated a strong link between EZH2 and the immune inflammatory response and oxidoreductase activity in PASMCs. mRNA expression levels of superoxide dismutase 3 were verified by qPCR. The results suggested that EZH2 was involved in the migration of PASMCs in PH, and may serve as a potential target for the treatment of PH.

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Section: Discussionsupporting

confidence: 92%

Effect of EZH2 on pulmonary artery smooth muscle cell migration in pulmonary hypertension

Wang

Huang²,

Dong

et al. 2020

Mol Med Rep

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“…Th17 cytokines are featured as IL-17 and GM-CSF. Th17 cells infiltration and IL-17 elevation are observed in the clinic and experimental PAH/PH ( 36 , 37 ). Over-expressing IL-17 or blocking IL-17 in mice regulates the PH development through directly affected PAECs and PASMCs function ( 37 ).…”

Section: Immune Cells Involved In Adaptive Immunitymentioning

confidence: 99%

Autoimmunity in Pulmonary Arterial Hypertension: Evidence for Local Immunoglobulin Production

Shu

Xing

Wang

2021

Front. Cardiovasc. Med.

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Pulmonary arterial hypertension (PAH) is a progressive life-threatening disease. The notion that autoimmunity is associated with PAH is widely recognized by the observations that patients with connective tissue diseases or virus infections are more susceptible to PAH. However, growing evidence supports that the patients with idiopathic PAH (IPAH) with no autoimmune diseases also have auto-antibodies. Anti-inflammatory therapy shows less help in decreasing auto-antibodies, therefore, elucidating the process of immunoglobulin production is in great need. Maladaptive immune response in lung tissues is considered implicating in the local auto-antibodies production in patients with IPAH. In this review, we will discuss the specific cell types involved in the lung in situ immune response, the potential auto-antigens, and the contribution of local immunoglobulin production in PAH development, providing a theoretical basis for drug development and precise treatment in patients with PAH.

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“…Consistent with published data, the enrichment of these DEGs in GO terms, such as leukocyte migration (20,21), collagencontaining ECM (22,23), cytokine activity (24,25), and antioxidant activity (26), confirms their involvement in the development of IPAH. Besides, enrichment of the identified DEGs in some KEGG pathways, such as the chemokine signaling pathway (24,25), IL-17 signaling pathway (27,28), and NFkappa B signaling pathway (29,30), also suggests the relevance in IPAH pathogenesis. Based on GO and KEGG analysis results, we suggest that these DEGs are closely associated with immune response and IPAH development.…”

Section: Discussionmentioning

confidence: 92%

Essential Genes and MiRNA–mRNA Network Contributing to the Pathogenesis of Idiopathic Pulmonary Arterial Hypertension

Hao

Jiang

Xie

et al. 2021

Front. Cardiovasc. Med.

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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 aggregation (RRA) method to integrate four eligible pulmonary arterial hypertension (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 interaction (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 miRNAs (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 the PAH animal model.Results: A total of 260 DEGs, consisting of 183 upregulated and 77 downregulated 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 is 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 top 10 hub genes with high connectivity degrees. WGCNA further identified five main functional modules involved in the pathogenesis of IPAH. Twelve upregulated DE-miRNAs and nine 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.

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Targeting IL-17 attenuates hypoxia-induced pulmonary hypertension through downregulation of β-catenin

Cited by 38 publications

References 51 publications

Effect of EZH2 on pulmonary artery smooth muscle cell migration in pulmonary hypertension

Effect of EZH2 on pulmonary artery smooth muscle cell migration in pulmonary hypertension

Autoimmunity in Pulmonary Arterial Hypertension: Evidence for Local Immunoglobulin Production

Essential Genes and MiRNA–mRNA Network Contributing to the Pathogenesis of Idiopathic Pulmonary Arterial Hypertension

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