Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Sphingosine kinase 1 regulates the pulmonary vascular immune response

ABSTRACT: Aberrant proliferation of pulmonary arterial smooth muscle (PASMCs) cells are a defining characteristic of pulmonary arterial hypertension (PAH) and leads to increased vascular resistance, elevated pulmonary pressure, and right heart failure. The Sphingosine kinase 1 (SPHK1)/Sphingosine-1 phosphate/ Sphingosine-1 phosphate receptor 2 pathway promotes vascular remodeling and induces PAH. The aim of this study was to identify genes and cellular processes that are modulated by over-expression of SPHK1 in human PASMCs (hPASMCs). RNA was purified and submitted for RNA sequencing to identify differentially expressed genes. Using a corrected p-value threshold of <0.05, there were 294 genes significantly up-regulated while 179 were significantly down-regulated. Predicted effects of these differentially expressed genes was evaluated using the freeware tool Enrichr to assess general gene set over-representation (enrichment) and Ingenuity Pathway Analysis (IPA™) for upstream regulator predictions. We found a strong change in genes that regulated the cellular immune response. IL6, STAT1, and PARP9, were elevated in response to SPHK1 over-expression in hPASMCs. The gene set enrichment mapped to a few immune modulatory signaling networks, including IFNG. Furthermore, STAT1 protein was elevated in primary hPASMCs isolated from PAH patients. In conclusion, these data suggest a role of Sphk1 regulates pulmonary vascular immune response in PAH.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174304 | GEO | 2021/06/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Unravelling AURKB as a potential therapeutic target in pulmonary arterial hypertension using integrated transcriptomic analysis and pre-clinical studies

Project description:To illuminate new actionable targets involved in pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), we performed RNA sequencing on pulmonary artery smooth muscle cells (PASMCs) isolated from PAH patients and control donors. We then enriched our own experiment with publicly available datasets. Aggregation of gene expression datasets followed by functional enrichment and connectivity map analyses on common upregulated genes in PAH-PASMCs revealed Aurora kinase B (AURKB), the enzymatic core of the chromosomal passenger complex with BIRC5, as a potential driver and therapeutic target in PAH. Using pharmacological and molecular tools, we demonstrated that inhibition of AURKB in PAH-PASMCs blocks cell cycle progression, induces cell death, and reverses the gene signature of PAH-PASMCs. In addition, we provided evidence that AURKBi-treated PAH-PASMCs that escape apoptosis, acquire a senescence-associated secretory phenotype. In vivo, AURKB inhibition using Barasertib significantly improved hemodynamics in two preclinical models of established PAH by attenuating pulmonary vascular remodeling. A therapeutic effect was also observed in precision-cut lung slices generated from human lungs, thus confirming the predictive value of AURKB interference as a potential therapeutic for PAH progression.Finally, we demonstrated that the combination of Barasertib with the anti-senescent agent UC2288 was more effective in reducing vascular remodeling than either drug alone.

2024-11-28 | GSE263226 | GEO

Pharmacological inhibition of G9a ameliorates pulmonary vascular remodeling in PAH

Project description:Background:Pulmonary arterial hypertension (PAH) is a severe condition characterized by progressive vascular remodeling of small pulmonary arteries (PAs) causing sustained elevation of PA pressure, right ventricular failure and death. Similar to cancer cells, PA smooth muscle cells (PASMCs), which play a key role in pulmonary vascular remodeling, have adopted multiple mechanisms to sustain their survival and proliferation in the presence of stress. The histone methyltransferase G9a has been shown to exert oncogenic effects and to serve as a buffer against an exaggerated transcriptional response. Therefore, we hypothesized that G9a up-regulation in PAH plays a pivotal role in pulmonary vascular remodeling by maintaining the abnormal phenotype of PAH-PASMCs. Methods: G9alevels were measured in PAs and isolated PASMCs of PAH patients and animal models. Selective G9a pharmacological inhibitors were used in human PAH-PASMCs and in rodent PAH models (i.e.Fawn-Hooded rats and Sugen/Hypoxia-exposed mice). Results: We present evidence of increased expression of G9a in PASMCs from PAH patients as well as in remodeled PAs from animal models. We found that pharmacological inhibition of G9a activity using BIX01294 and UNC0642significantly reduces the prosurvival and proproliferative potentials of cultured PAH-PASMCs. Using RNA sequencing, further exploration revealed that G9a promotes extracellular matrix production and affords protection against the negative effects of an overactive stress response. Finally, we found that therapeutic treatment with BIX01294 reduced pulmonary vascular remodeling and lowered mean PA pressure in Fawn-Hooded rats. Treatment of Sugen/hypoxia-challenged mice with BIX01294 also improved pulmonary hemodynamics and right ventricular function. Conclusions:These findings suggest that G9a inhibition may represent a new therapeutic approach in PAH.

2023-01-20 | GSE200821 | GEO

Next Generation Sequencing of Wild Type and CMG2-/- Rat Lung Transcriptomes

Project description:Purpose:Pulmonary arterial hypertension secondary to congenital heart disease (CHD-PAH) with systemic-to-pulmonary shunt is characterized by proliferative vascular remodeling. Capillary morphogenesis gene-2 (CMG2) exhibits roles in cell proliferation and apoptosis. The purpose of this study was to determine the possible roles of CMG2 in the pathogenesis of systemic-to-pulmonary shunt induced PAH. Methods Lung tissue sections from CHD-PAH patients, systemic-to-pulmonary shunt induced PAH rat model, CMG2-/- rats, and PASMCs were used. Immunohistochemistry, real time polymerase chain reaction, Western blot, proliferation, apoptosis, and next generation sequencing (NGS) were performed in this study. Results CMG2 expression was reduced in lung tissues and pulmonary arterioles from Eisenmenger’s syndrome patient and rats with systemic-to-pulmonary shunt induced PAH. CMG2-/- rats exhibited heavier PAH and pulmonary vascular remodeling following exposure to systemic-to-pulmonary shunt for 8 weeks. Over-expression of CMG2 in cultured human PASMCs inhibited cell proliferation and promoted apoptosis, while knockdown of CMG2 promoted cell proliferation and inhibited apoptosis. A total of 1319 genes were found to be dysregulated in CMG2-/- rat lungs as detected by NGS. Biological processes influenced by these differentially expressed genes include regulation of blood vessel diameter, vasoconstriction, regulation of blood vessel size, vascular process in circulatory system, etc., and the most prominent pathway regulated is PI3K-Akt signaling pathway. Conclusion Our work identifies a novel role for CMG2 in systemic-to-pulmonary shunt induced PAH based on the findings that CMG2 deficiency could exacerbate systemic-to- pulmonary shunt induced vascular remodeling in the development of PAH. CMG2 may be a potential target for CHD-PAH treatment.

2022-12-13 | GSE142118 | GEO

Transcriptome analysis of cultured human pulmonary artery smooth muscle cells (hPASMCs) to explore functional roles for CD26/DPP4 in stimulation with TGF-β1

Project description:The purpose of this study was to evaluate the role of CD26/DPP4 in hPASMCs in response to TGF-β1. In experimental methods, hPASMCs were treated as follows. The hPASMCs were cultured in Smooth Muscle Cell Growth Medium 2 with 10% fetal bovine serum and were incubated at 37 ℃ in a 5% CO2 incubator. The cells at passage 6 were used for all experiments. The PASMCs were treated with CD26/DPP4 siRNA or non-specific control siRNA for 48 hours, then stimulated with TGF-β1 or PBS for 24 hours. Transcriptome analysis revealed that TGFβ treatment in cultured hPASMCs upregu-lated genes related to pulmonary vascular SMC proliferation, involving the Notch, PI3K-Akt, and NFκB signaling pathways.Conversely, DPP4-siRNA treatment in cultured hPASMCs downregulated these pathways.

2024-01-03 | GSE248794 | GEO

Transcriptomics and proteomics revealed sex differences in human pulmonary microvascular endothelial cells

Project description:There is marked sexual dimorphism displayed in the onset and progression of pulmonary hypertension (PH). Females more commonly develop pulmonary arterial hypertension (PAH), however, females with PAH and other types of PH have better survival than males. Pulmonary microvascular endothelial cells play a crucial role in the pulmonary vascular remodelling and increased pulmonary vascular resistance of PH. Given this background, we hypothesized that there are sex differences in the pulmonary microvascular endothelium basally and in response to hypoxia that are independent of the sex hormone environment.

2024-01-03 | PXD046787 | Pride

Murine pulmonary arterial smooth muscle cells: Wild-type vs. NOX1 deficiency (miRNA profiling)

Project description:NOX1 is a catalytic subunit of nonphagocytic NADPH oxidase, mainly localized to smooth muscle cells in the vasculature. We investigated the pathology underlying the pulmonary arterial hypertension-like phenotype demonstrated in mice deficient in the Nox1 gene (Nox1-KO). Spontaneous enlargement and hypertrophy of the right ventricle, accompanied by hypertrophy of pulmonary vessels, were demonstrated in Nox1-KO at 9-18 weeks of age. Since an increased number of ?-smooth muscle actin-positive vessels was observed in Nox1-KO, pulmonary arterial smooth muscle cells (PASMCs) were isolated and characterized by flow cytometry and TUNEL staining. In Nox1-/Y PASMC, the number of apoptotic cells was significantly reduced without any change in the expression of endothelin-1, and hypoxia-inducible factors HIF-1a and HIF-2a, factors implicated in the pathogenesis of PAH. microRNA expression profiling of mouse pulmonary arterial smooth muscle cells in wild-type and NOX1-KO was analyzed. Pulmonary arterial smooth muscle cells were harvested form 3 mice.

2014-01-22 | E-GEOD-42015 | biostudies-arrayexpress

Murine pulmonary arterial smooth muscle cells: Wild-type vs. NOX1 deficiency (mRNA profiling)

Project description:NOX1 is a catalytic subunit of nonphagocytic NADPH oxidase, mainly localized to smooth muscle cells in the vasculature. We investigated the pathology underlying the pulmonary arterial hypertension-like phenotype demonstrated in mice deficient in the Nox1 gene (Nox1-KO). Spontaneous enlargement and hypertrophy of the right ventricle, accompanied by hypertrophy of pulmonary vessels, were demonstrated in Nox1-KO at 9-18 weeks of age. Since an increased number of α-smooth muscle actin-positive vessels was observed in Nox1-KO, pulmonary arterial smooth muscle cells (PASMCs) were isolated and characterized by flow cytometry and TUNEL staining. In Nox1-/Y PASMC, the number of apoptotic cells was significantly reduced without any change in the expression of endothelin-1, and hypoxia-inducible factors HIF-1a and HIF-2a, factors implicated in the pathogenesis of PAH. Transcriptional profiling of mouse pulmonary arterial smooth muscle cells in wild-type and NOX1-KO was analyzed. Pulmonary arterial smooth muscle cells were harvested from 3 mice.

2014-01-22 | E-GEOD-42014 | biostudies-arrayexpress

Epigenome-wide profiling uncovers novel pathway networks in human pulmonary arterial hypertension [pul36]

2022-06-09 | GSE194080 | GEO

Metabolomic heterogeneity of severe pulmonary arterial hypertension

Project description:Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of severe PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH in its later stage, which may differ from the earlier stage of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH. Global profiles were determined in human lung tissue and compared across 11 normal and 12 severe pulmonary arterial hypertension patients. Using a combination of microarray and high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung.

2014-11-14 | E-GEOD-53408 | biostudies-arrayexpress

Epigenome-wide profiling uncovers novel pathway networks in human pulmonary arterial hypertension [pul28]

Project description:Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease that culminates in right heart failure. Vascular pathology in PH is characterized by pulmonary vasoconstriction and progressive vascular remodeling processes that affects all layers of the vascular wall (intima, media and adventitia). Our objective was to profile and analyze the differential gene expression signatures between the cells isolated from normal and idiopathic PAH patients. We generated vascular cell-specific transcriptome profiles from the adventitial fibroblasts (PAAF) isolated ex vivo from the dissected human pulmonary arteries of normal donor and PAH lungs using paired-end RNA-sequencing.

2022-06-09 | GSE193776 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data