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Genome-wide mapping of p53-transcriptional activity in the pulmonary endothelium [ChIP-seq]

ABSTRACT: We report a pharmacologically inducible vasculoprotective mechanism in pulmonary arterial endothelial cells (PAEC) in response to DNA damage by p53 and a novel PPARgamma/p53 transcription factor complex.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139858 | GEO | 2021/03/03

REPOSITORIES: GEO

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Genome-wide mapping of p53-transcriptional activity in the pulmonary endothelium [RNA-seq]

Project description:We report a pharmacologically inducible vasculoprotective mechanism in pulmonary arterial endothelial cells (PAEC) in response to DNA damage by p53 and a novel PPARgamma/p53 transcription factor complex.

2021-03-03 | GSE139862 | GEO

Reduced FOXF1 Links Unrepaired DNA Damage to Pulmonary Arterial Hypertension

Project description:Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common mutant gene in PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxic exposure (reoxygenation), as do mice with EC deletion of Bmpr2 (EC-Bmpr2-/-) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm-/-). Gene expression analysis of EC-Atm-/- and EC-Bmpr2-/- lung EC revealed reduced Foxf1, a transcription factor with relative selectivity for lung EC. Reducing FOXF1 in control PAEC induced DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repaired DNA damage and restored angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2-/- mice repaired DNA damage, induced angiogenesis and reversed pulmonary hypertension.

2023-08-15 | GSE215933 | GEO

P53-dependent Genes in Human Pulmonary Adventitial Fibroblasts

Project description:We report differentially expressed genes in human pulmonary arterial adventitial fibroblasts under genotoxic stress (Doxorubicin) or pharmacological p53-activation by Nutlin-3.

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P53-dependent Genes in Human Pulmonary Smooth Muscle Cells

Project description:We report differentially expressed genes in human pulmonary arterial smooth muscle cells under genotoxic stress (Doxorubicin) or pharmacological p53-activation by Nutlin-3.

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Monocytes Release Endogenous Retroviral Protein in Exosomes Causing a Mesenchymal, Proinflammatory Endothelium and Pulmonary Hypertension

Project description:Human endogenous retroviral (HERV) proteins are induced by exogenous viruses or other factors that derepress HERV transcription and translation. Previously we showed that HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) proteins are increased in monocytes and macrophages from patients with pulmonary arterial hypertension (PAH). Recombinant HERV-K dUTPase upregulates IL6 in pulmonary arterial endothelial cells (PAECs) and induces pulmonary hypertension in rats. However, it was not known how HERV-K dUTPase released from monocytes engages PAECs to upregulate IL6 or induces other PAH features of PAEC dysfunction. Here we report that HERV-K dUTPase recruits TLR4-myeloid differentiation primary response-88 to increase IL6 and SNAIL, the endothelial-mesenchymal transition (EndMT) transcription factor; HERV-K dUTPase interaction with melanoma cell adhesion molecule (MCAM) upregulates VCAM1. p38 and NF-kB are required to increase expression of all three genes, but in addition, pJNK-pSMAD3 is necessary for SNAIL upregulation, STAT1 for IL6, and pERK1/2-activating transcription factor-2 for VCAM1. Packaging of HERV-K dUTPase in monocyte-derived extracellular vesicles (EVs) induces SNAIL and subsequent EndMT in PAECs, IL6 and VCAM1. Mice infused with EVs from monocytes transfected with HERV-K dUTPase develop pulmonary hypertension. Thus, retroviral proteins delivered in EVs can overtake PAEC signaling and transcriptional machinery to induce dysfunction associated with PAH.

2020-08-24 | MSV000086005 | MassIVE

Genome-wide mapping of p53-transcriptional activity in the pulmonary endothelium

Project description:Genome-wide mapping of p53-transcriptional activity in the pulmonary endothelium

| PRJNA587160 | ENA

Genome-wide mapping of p53-transcriptional activity in the pulmonary endothelium [ChIP-seq]

Project description:Genome-wide mapping of p53-transcriptional activity in the pulmonary endothelium [ChIP-seq]

| PRJNA587155 | ENA

Genome-wide mapping of p53-transcriptional activity in the pulmonary endothelium [RNA-seq]

Project description:Genome-wide mapping of p53-transcriptional activity in the pulmonary endothelium [RNA-seq]

| PRJNA587156 | ENA

Transcriptional Profiles of Pulmonary Artery Endothelial Cells in Pulmonary Hypertension

Project description:Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene expression of pulmonary artery ECs (PAECs) can discern disease subtypes, progression and pathogenesis. We aimed to further validate our previously described method to propagate ECs from right heart catheter (RHC) balloon tips and to perform additional PAEC phenotyping. We performed bulk RNA sequencing of PAECs from RHC balloons. Using unsupervised dimensionality reduction and clustering we compared transcriptional signatures from PAH to controls and other forms of pulmonary hypertension. Select PAEC samples underwent single cell and population growth characterization and anoikis quantification. Fifty-four specimens were analyzed from 49 subjects. The transcriptome appeared stable over limited passages. Six genes involved in sex steroid signaling, metabolism, and oncogenesis were significantly upregulated in PAH subjects as compared to controls. Genes regulating BMP and Wnt signaling, oxidative stress and cellular metabolism were differentially expressed in PAH subjects. Changes in gene expression tracked with clinical events in PAH subjects with serial samples over time. Functional assays demonstrated enhanced replication competency and anoikis resistance. Our findings recapitulate fundamental biological processes of PAH and provide new evidence of a cancer-like phenotype in ECs from the central vasculature of PAH patients. This “cell biopsy” approach may provide insight into EC heterogeneity within the lung and a therapeutic screening approach in PAH.

2023-12-27 | GSE243193 | GEO

Acquired chromosome abnormalities in the lungs of patients with Pulmonary Arterial Hypertension (Illumina)

Project description:Vascular remodeling in pulmonary arterial hypertension (PAH) involves proliferation and migration of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Previous studies have indicated that the endothelial cell proliferation is quasi-neoplastic, with evidence of monoclonality and instability of short DNA microsatellite sequences. To assess whether there is larger scale genomic instability, we performed genome-wide microarray copy number analysis on pulmonary artery endothelial (PAEC) and smooth muscle cells isolated from the lungs of PAH patients. Mosaic chromosomal abnormalities were detected in five of nine PAEC cultures from PAH lungs and zero of four controls. Fluorescent in situ hybridization analysis confirmed the presence of these abnormalities in vivo in two of three cases. One patient harbored a germline mutation of BMPR2, the primary genetic cause of PAH, and a somatic loss of chromosome-13, which constitutes a second hit in the same pathway by deleting Smad-8. In two female cases with mosaic loss of the X-chromosome, methylation analysis showed that the active X was deleted. Remarkably, one also showed completely skewed X-inactivation in the non-deleted cells, suggesting the PAEC population was clonal prior to the acquisition of the chromosome abnormality. Our data indicate a high frequency of genetically abnormal sub-clones within the lung vessels of patients with PAH and provide the first definitive evidence of a second genetic hit in a patient with a germline BMPR2 mutation. We propose that these chromosome abnormalities may confer a growth advantage and thus contribute to the progression of PAH. Cross-sectional study of genomic copy number in cells cultured from the lungs of PAH patients.

2010-05-01 | E-GEOD-21097 | biostudies-arrayexpress

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