Pulmonary endothelial cell DNA methylation signature in pulmonary arterial hypertension

Hautefort, Aurélie; Chesné, Julie; Preussner, Jens; Pullamsetti, Soni Savai; Tost, Jörg; Looso, Mario; Antigny, Fabrice; Girerd, Barbara; Riou, Marianne; Eddahibi, Saadia; Deleuze, Jean‐François; Seeger, Werner; Fadel, Élie; Simonneau, Gérald; Montani, David; Humbert, Marc; Perros, Frédèric

doi:10.18632/oncotarget.18031

Cited by 42 publications

(46 citation statements)

References 84 publications

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“…In our view, this ectopic gene expression is due to a pathological Darwinian evolution process evolving on the fertile ground of genome-wide epigenetic modifications already suggested in PAH. 12 – 16 This observation of an identity crisis in PAH strengthens the parallels that can be established between the PAH condition and cancer where a similar finding has been reported.…”

Section: Discussionsupporting

confidence: 85%

“… 10 , 11 Finally, there is growing evidence for genome-wide epigenetic modifications in PAH that lead to chromatin remodeling and gene expression alterations. These modifications include varied expression of epigenetic modifiers and readers including histone deacetylases (HDACs) 12 and BRD4, 13 DNA methylation modifications, 14 , 15 and microRNAs. 16 …”

Section: Introductionmentioning

confidence: 99%

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Identity crisis in pulmonary arterial hypertension

et al. 2017

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Identity crisis in pulmonary arterial hypertension

et al. 2017

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“…Recent published work proposes that modulated NKX2‐5 expression is implicated in vascular homeostasis and vascular disease–associated phenotypes 39, 40, 41. In our previous studies, we demonstrated a critical role of NKX2‐5 in vascular remodeling and atherosclerosis, with expression being detected in atherosclerotic lesions, in the fibrous cap, and in the cells within the media 5, 6.…”

Section: Discussionmentioning

confidence: 74%

Molecular Basis for Dysregulated Activation of NKX2‐5 in the Vascular Remodeling of Systemic Sclerosis

Dritsoula

Guerra

Fonseca

et al. 2018

Arthritis & Rheumatology

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Objective NKX2‐5 is a homeobox transcription factor that is required for the formation of the heart and vessels during development, with significant postnatal down‐regulation and reactivation in disease states, characterized by vascular remodeling. The purpose of this study was to investigate mechanisms that activate NKX2‐5 expression in diseased vessels, such as systemic sclerosis (scleroderma; SSc)–associated pulmonary hypertension (PH), and to identify genetic variability that potentially underlies susceptibility to specific vascular complications.MethodsWe explored NKX2‐5 expression in biopsy samples from patients with SSc‐associated PH and in pulmonary artery smooth muscle cells (PASMCs) from patients with scleroderma. Disease‐associated putative functional single‐nucleotide polymorphisms (SNPs) at the NKX2-5 locus were cloned and studied in reporter gene assays. SNP function was further examined through protein–DNA binding assays, chromatin immunoprecipitation assays, and RNA silencing analyses.ResultsIncreased NKX2‐5 expression in biopsy samples from patients with SSc‐associated PH was localized to remodeled vessels and PASMCs. Meta‐analysis of 2 independent scleroderma cohorts revealed an association of rs3131917 with scleroderma (P = 0.029). We demonstrated that disease‐associated SNPs are located in a novel functional enhancer, which increases NKX2-5 transcriptional activity through the binding of GATA‐6, c‐Jun, and myocyte‐specific enhancer factor 2C. We also characterized an activator/coactivator transcription‐enhancer factor domain 1 (TEAD1)/Yes‐associated protein 1 (YAP1) complex, which was bound at rs3095870, another functional SNP, with TEAD1 binding the risk allele and activating the transcription of NKX2-5.Conclusion NKX2-5 is genetically associated with scleroderma, pulmonary hypertension, and fibrosis. Functional evidence revealed a regulatory mechanism that results in NKX2-5 transcriptional activation in PASMCs through the interaction of an upstream promoter and a novel downstream enhancer. This mechanism can act as a model for NKX2‐5 activation in cardiovascular disease characterized by vascular remodeling.

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“…A high level of Met could hypermethylate DNA and then produce undesirable epigenetic effects. DNA methylation contributes to the pathogenesis of pulmonary diseases, including cancer and PAH [ 54 ], in particular by promoting phenotypic changes in hPAECs in PAH [ 55 ]. Alterations in the DNA methylation of the SOD2 gene (Superoxyde dismutase 2) are known to reduce the expression of SOD2, which is related to pulmonary vascular cell proliferation, apoptosis resistance, and cell metabolic changes [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells

Ribeuz

Dumont

Ruellou

et al. 2020

IJMS

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The physiopathology of pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) and endothelial cell (PAEC) dysfunction, contributing to pulmonary arterial obstruction and PAH progression. KCNK3 loss of function mutations are responsible for the first channelopathy identified in PAH. Loss of KCNK3 function/expression is a hallmark of PAH. However, the molecular mechanisms involved in KCNK3 dysfunction are mostly unknown. To identify the pathological molecular mechanisms downstream of KCNK3 in human PASMCs (hPASMCs) and human PAECs (hPAECs), we used a Liquid Chromatography-Tandem Mass Spectrometry-based proteomic approach to identify the molecular pathways regulated by KCNK3. KCNK3 loss of expression was induced in control hPASMCs or hPAECs by specific siRNA targeting KCNK3. We found that the loss of KCNK3 expression in hPAECs and hPASMCs leads to 326 and 222 proteins differentially expressed, respectively. Among them, 53 proteins were common to hPAECs and hPASMCs. The specific proteome remodeling in hPAECs in absence of KCNK3 was mostly related to the activation of glycolysis, the superpathway of methionine degradation, and the mTOR signaling pathways, and to a reduction in EIF2 signaling pathways. In hPASMCs, we found an activation of the PI3K/AKT signaling pathways and a reduction in EIF2 signaling and the Purine Nucleotides De Novo Biosynthesis II and IL-8 signaling pathways. Common to hPAECs and hPASMCs, we found that the loss of KCNK3 expression leads to the activation of the NRF2-mediated oxidative stress response and a reduction in the interferon pathway. In the hPAECs and hPASMCs, we found an increased expression of HO-1 (heme oxygenase-1) and a decreased IFIT3 (interferon-induced proteins with tetratricopeptide repeats 3) (confirmed by Western blotting), allowing us to identify these axes to understand the consequences of KCNK3 dysfunction. Our experiments, based on the loss of KCNK3 expression by a specific siRNA strategy in control hPAECs and hPASMCs, allow us to identify differences in the activation of several signaling pathways, indicating the key role played by KCNK3 dysfunction in the development of PAH. Altogether, these results allow us to better understand the consequences of KCNK3 dysfunction and suggest that KCNK3 loss of expression acts in favor of the proliferation and migration of hPASMCs and promotes the metabolic shift and apoptosis resistance of hPAECs.

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Pulmonary endothelial cell DNA methylation signature in pulmonary arterial hypertension

Cited by 42 publications

References 84 publications

Identity crisis in pulmonary arterial hypertension

Identity crisis in pulmonary arterial hypertension

Molecular Basis for Dysregulated Activation of NKX2‐5 in the Vascular Remodeling of Systemic Sclerosis

Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells

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