Comparing CTEPH to Control and IPAH pulmonary arteries
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE130391 | GEO | 2019/04/27
REPOSITORIES: GEO
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Project description:Comparing CTEPH to Control and IPAH pulmonary arteries
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Project description:The hallmark of chronic thromboembolic pulmonary hypertension (CTEPH) is fibrotic transformation of pulmonary arterial thrombus, leading to mechanical obstruction of pulmonary arteries. We report the transcriptome profile of fibroblasts isolated from pairs of CTEPH thrombus and pulmonary artery adventitia of the same patient. Fibroblasts isolated from CTEPH thrombus demonstrated upregulation of genes associated with the TGF-β pathway indicating that TGF-β upregulation is associated with the intravascular remodeling process.
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Project description:Idiopathic Pulmonary Arterial Hypertension (IPAH) is a severe human disease, characterized by extensive pulmonary vascular remodeling due to plexiform and obliterative lesions, media hypertrophy, and alterations of adventitia. The objective of the study was to test the hypothesis that microscopic IPAH vascular lesions express unique molecular profiles, which collectively are different from control pulmonary arteries. We used digital spatial transcriptomics to profile the genome-wide differential transcriptomic signature of key pathological lesions (plexiform, obliterative, intima+media hypertrophy, and adventitia) in IPAH lungs (n= 11) and compared these data to the intima+media and adventitia of control pulmonary artery (n=5). The IPAH lesions and pulmonary artery compartments were defined by the analyses of hematoxylin-eosin stained serial section, aided by labeling with CD31 (for endothelial cells), smooth muscle cell actin (SMA), and CD45 for inflammatory mononuclear cells, also in serial sections. Approximately 12 regions of interest (ROI) were sampled from a histological section of a paraffin-embedded block of each lung, which was selected based on the finding of enrichment for IPAH lesions or control pulmonary arteries.
2024-04-04 | GSE256539 | GEO
Project description:Pulmonary hypertension worsens outcome in left heart disease. Stiffening of the pulmonary artery may drive this pathology by increasing right ventricular dysfunction and lung vascular remodeling. We showed that pulmonary arteries from patients with left heart disease are characterized by increased stiffness that correlates with impaired pulmonary hemodynamics. Pulmonary arteries in left heart disease patients with pulmonary hypertension were characterized by degradation of elastic fibers paralleled by an accumulation of fibrillar collagens. We utilized RNA sequencing to identify differentially expressed genes regulating extracellular matrix remodeling in pulmonary arteries of left heart disease patients with or without pulmonary hypertension, in comparison to healthy-heart donor controls. As such we identified that transcriptional deregulation of extracellular matrix constituents and their regulators precedes clinical pulmonary hypertension, and therefore might be a pathomechanism that drives pulmonary arterial remodeling and stiffening in left heart disease.
2023-07-03 | GSE236251 | GEO
Project description:Whole genome microRNA microarray expression profiling was employed as a discovery platform to identify microRNAs dysregulated in end-stage idiopathic pulmonary arterial hypertension (IPAH) patients. Lung tissue from seven IPAH patients and eight failed donor controls were subjected to microarray screening. Twenty-one miRNAs were identified dyeregulated in IPAH patients compared to controls. In miRNA real-time PCR validation, 22 IPAH patients and 22 control subjects were enrolled, including the 7 IPAH and 8 controls in microarray screening. Expression levels of five miRNAs (let-7a-5p, miR-199a-3p, miR-199b-5p, miR-26b-5p and miR-27b-3p) were upregulated in technical validation. Tissue miRNA levels had positive correlation with pulmonary vascular remodeling and hemodynamic changes in IPAH patients compared to controls.
2017-08-23 | GSE67597 | GEO
Project description:Chronic thromboembolic pulmonary hypertension (CTEPH) is a group 4 pulmonary hypertension (PH) characterized by non-resolving thromboembolism in the central pulmonary artery and vascular occlusion in the proximal and distal pulmonary artery. Medical therapy is chosen for patients who are ineligible for pulmonary endarterectomy or balloon pulmonary angioplasty or who have symptomatic residual PH after surgery or intervention. Selexipag, an oral prostacyclin receptor agonist and potent vasodilator, was approved for CTEPH in Japan in 2021. To evaluate the pharmacological effect of selexipag on vascular occlusion in CTEPH, we examined how its active metabolite MRE-269 affects platelet-derived growth factor-stimulated pulmonary arterial smooth muscle cells (PASMCs) from CTEPH patients. MRE-269 showed a more potent anti-proliferative effect on PASMCs from CTEPH patients than on those from normal subjects. DNA-binding protein inhibitor genes ID1 and ID3 were found by RNA sequencing and real-time quantitative polymerase chain reaction to be expressed at lower levels in PASMCs from CTEPH patients than in those from normal subjects and were upregulated by MRE-269 treatment. ID1 and ID3 upregulation by MRE-269 was blocked by co-incubation with a prostacyclin receptor antagonist, and ID1 knockdown by small interfering RNA transfection attenuated the anti-proliferative effect of MRE-269. ID signaling may be involved in the anti-proliferative effect of MRE-269 on PASMCs. This is the first study to demonstrate the pharmacological effects on PASMCs from CTEPH patients of a drug approved for the treatment of CTEPH. Both the vasodilatory and the anti-proliferative effect of MRE-269 may contribute to the efficacy of selexipag in CTEPH.
2022-12-27 | GSE221511 | GEO
Project description:Dysfunction of pulmonary arterial endothelial cells (PAECs) is associated with the development and progression of vascular pathology. However, it remains unknown how pulmonary hypertension (PH) affects cellular composition and transcriptomic profile of pulmonary endothelium. Here, we have undertaken a single-cell, compartment specific approach to characterise alterations in PAECs associated with two different types of PH, i.e., pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with pulmonary fibrosis (PHPF). Our unbiased analysis showed that endothelium of medium / small caliber pulmonary arteries is composed of three subsets of endothelial cells (ECs). The analysis of healthy and PH endothelium revealed that the three populations are persistently represented in remodelled arteries. Additionally, an exploratory analysis of human aorta (AO) and coronary arteries (CA) endothelium revealed that, although similar gene expression patterns were noticeable, PAECs subpopulations proportions differs significantly from pulmonary arteries (PA) endothelium. To address whether EC heterogeneity is a prime feature of human endothelium, we also performed a similar analysis in a murine model of hypoxia, revealing that similar EC populations were evident in this animal model. Comparative analysis of EC subpopulations in healthy and PH EC identified a common genetic deregulation accompanying vascular remodelling. Even though murine EC displayed some similarities with human EC subpopulations, the intense re-programming associated with hypoxia associated vascular remodelling displayed significant differences compared to the human disease. Finally, in depth comparative analysis of PAH and PHPF EC highlighted the development of disease-specific transcriptomic alterations in the three populations. Therefore, characterisation of transcriptomic differences in the endothelial bed of PAH and PHPF patients can facilitate identification of novel, disease-specific therapeutic targets.
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Project description:Bone morphogenetic proteins (BMP) inhibit proliferation and induce apoptosis in pulmonary artery smooth muscle cells (PASMC) from normal subjects. Dysfunction of BMP signaling due to mutations in and/or downregulation of BMP receptors has been implicated in idiopathic pulmonary arterial hypertension (IPAH). We examined whether BMP differentially regulates gene expression in PASMC from normal subjects and IPAH patients using the Affymetrix microarray analysis. BMP-2 treatment (200 nM for 24 hrs) altered expression levels of 6,206 genes in normal and IPAH PASMC. 1,063 of these genes were regulated oppositely by BMP-2: 523 genes were downregulated by BMP-2 in normal PASMC but upregulated in IPAH PASMC, whereas 540 genes were upregulated by BMP-2 in normal PASMC but downregulated in IPAH PASMC. The divergent effects of BMP-2 on gene expression profiles indicate that PASMC may undergo significant phenotypic changes in IPAH patients during development of the disease. The transition of the antiproliferative effect of BMP-2 in normal PASMC to its proliferative effect in IPAH patients is attributed potentially to its differential effect on expression patterns of various genes that are involved in cell proliferation and apoptosis. Among the 6206 BMP-2-sensitive genes, there are more than 1800 genes whose expression levels were negatively (with a correlation coefficient, r, < –0.9) or positively (with r > +0.9) correlated with the pulmonary arterial pressure. These results suggest that BMP-mediated gene regulation is significantly altered in PASMC from IPAH patients and mRNA expression changes in BMP-regulated genes may be involved in the development of IPAH. Keywords = bone morphogenetic receptor protein Keywords = idiopathic pulmonary arterial hypertension Keywords = transcription factor Keywords = gene expression profile Keywords: other
2005-10-21 | GSE2559 | GEO
Project description:We performed RNA-seq to analyze gene expression in human PASMCs (Pulmonary arterial smooth muscle cells) isolated from subjects without disease and from subjects with IPAH (idiopathic pulmonary hypertension)
2020-07-15 | GSE144274 | GEO