Serial mRNA profiling of peripheral blood monocytes from PAH patients treated with phosphodiesterase 5 inhibitors (PDE5i) and PDE5i+macitentan
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ABSTRACT:
PROVIDER: PRJNA999735 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25453913_1.fastq.gz | Fastqsanger.gz | |||
| SRR25453913_2.fastq.gz | Fastqsanger.gz | |||
| SRR25453914_1.fastq.gz | Fastqsanger.gz | |||
| SRR25453914_2.fastq.gz | Fastqsanger.gz | |||
| SRR25453915_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: We performed single cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from non-diseased control individuals (N=3) as well as from individuals with PAH, naïve to treatment (N=4), 3 months after phosphodiesterase 5 inhibitor (PDE5i) treatment (N=5), and 3 months after treatment with PDE5i plus an endothelin receptor antagonist, macitentan (N=5). We performed complementary analyses of differential gene expression and differential gene network dependency. Method: Blood samples collected in EDTA purple top vacutainer were centrifuged at 2000 RPM for 15 minutes and plasma was removed for banking. Buffy coats were collected and used for Ficoll gradient to isolate PBMC which are used for the single cell RNA sequencing analysis. RNA libraries were prepared using Chromium Single Cell 3’ Reagent Kits V2 per manufacturer’s guidelines (10x Genomics manual CG00052, cat# PN-12237). Single cell RNA-sequencing was performed using the GemCodeTM Single Cell Instrument (Chromium, 10X Genomics) which included at least 800 cells (~50K reads per cell) per N=3 non-PAH control samples, N=4 PAH no treatment samples, N=8 PDE5i treated samples, and N=6 PDE5i+Macitentan treated samples.
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Project description:Pulmonary Arterial Hypertension (PAH) is characterized by progressive increase in pulmonary vascular resistance, right ventricular failure and premature death. Owing to severe complications, lung biopsies cannot be envisioned to characterize the disease. Based on the prominent role of inflammation in PAH development, we used Peripheral Blood Mononuclear Cells (PBMCs) as cell source, and relied on the SOLiD platform of Serial Analysis of Gene Expression (SAGE) for transcriptional profiling
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Project description:Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury Forty-nine PBMC samples were obtained from 21 lSSc subjects without PAH (lSSc-noPAH), 15 lSSc subjects with PAH (lSSc-PAH), and 10 healthy controls; three subjects provided PBMCs one year later. Genome-wide gene expression was measured for each sample. Gene expression clearly distinguished lSSc samples from healthy controls, and separated lSSc-PAH from lSSc-NoPAH patients. The gene expression and cytokine profiles of lSSc-PAH patients suggest the presence of activated monocytes, and show markers of vascular injury and inflammation.
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2023-01-27 | GSE140948 | GEO
Project description:Introduction. Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disease that may be triggered by exposure to drugs such as dasatinib or facilitated by genetic predispositions. The incidence of dasatinib-associated PAH is estimated at 0.45%, suggesting individual predispositions. The mechanisms of dasatinib-associated PAH are still incomplete. This study studied the link between dasatinib and KCNK3 and the consequences of dasatinib exposure or KCNK3 knockdown in pulmonary endothelial cells (PECs) and pulmonary arterial smooth muscle cells (PASMC). Methods. We discovered a KCNK3 gene variant in a patient with dasatinib-associated PAH and investigated the impact of this variant on KCNK3 function using patch-clamp analysis. Additionally, we assessed the effects of dasatinib exposure on KCNK3 expression and function in human and rat pulmonary arteries. In control-human PASMCs and PECs (hPASMCs and hPECs), we evaluated the consequence of KCNK3 knockdown on cell migration, mitochondrial membrane potential, ATP production, and in vitro tube formation. Using mass spectrometry, we determined the KCNK3 interactome. Results. Patch-clamp revealed that the identified KCNK3 variant represents a loss-of-function variant. Dasatinib contributed to pulmonary artery constriction by decreasing KCNK3 function and expression. In control-hPASMCs, KCNK3 knockdown promotes mitochondrial membrane depolarization and glycolytic shift. Additionally, dasatinib exposure or KCNK3 knockdown reduced the number of caveolae in PECs. Moreover, KCNK3 knockdown in control-hPECs reduced migration, proliferation, and in vitro tubulogenesis. Lastly, using proximity ligation assay and mass spectrometry, we identified the KCNK3 interactome revealing that KCNK3 interaction with various proteins across different cellular compartments could impact these cellular functions. Conclusion. We identified a novel pathogenic variant in the KCNK3 gene, suggesting that KCNK3 gene variations could also influence the development of dasatinib-associated PAH. Our results support that one of the mechanisms of action of dasatinib-associated PAH results from the downregulation of KCNK3.
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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.
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