BMPR2 vs hypoxic pulmonary hypertension
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE2773 | GEO | 2005/06/10
SECONDARY ACCESSION(S): PRJNA92307
REPOSITORIES: GEO
Similar Datasets
Project description:Comparison of lung from hypoxic PAH to SM22-tet-BMPR2delx4+ PAH, with three different types of control Experiment Overall Design: One chip each of five conditions, with pooled RNA on each chip to reduce individual variability
2008-06-12 | E-GEOD-2773 | biostudies-arrayexpress
Project description:Familial pulmonary arterial hypertension (fPAH) is associated with mutations in BMPR2. Many of these mutations occur in the BMPR2 tail domain, leaving the SMAD functions intact. In order to determine the in vivo consequences of BMPR2 tail domain mutation, we created a smooth-muscle specific doxycycline inducible BMPR2 mutation with an arginine to termination mutation at amino acid 899. When these SM22-rtTA x TetO7-BMPR2R899X mice had transgene induced for 9 weeks, starting at 4 weeks of age, they universally developed pulmonary vascular pruning as assessed by fluorescent microangiography. Approximately half the time the induced animals developed elevated right ventricular systolic pressures (RVSP), associated with extensive pruning, muscularization of small pulmonary vessels, and development of large structural pulmonary vascular changes. These lesions included large numbers of macrophages and T-cells in their adventitial compartment, as well as CD133 positive cells in the lumen. Small vessels filled with CD45 positive and sometimes CD3 positive cells were a common feature in all SM22-rtTA x TetO7-BMPR2R899X mice. Gene array experiments show changes in stress response, muscle organization and function, proliferation and apoptosis, and developmental pathways before RVSP increases. Our results show that the primary phenotypic result of BMPR2 tail domain mutation in smooth muscle is pulmonary vascular pruning leading to elevated RVSP, associated with early dysregulation in multiple pathways with clear relevance to PAH. This model should be useful to the research community in examining early molecular and physical events in the development of PAH, and as a platform to validate potential treatments. Experiment Overall Design: Each array is an individual female mouse, age-matched, with two mice & arrays used for each of controls (transactivator only), BMPR2-R899X with normal RVSP, and BMPR2-R899X with high RVSP.
2008-06-18 | E-GEOD-11018 | biostudies-arrayexpress
Project description:Studies in various animal models suggest an important role for pulmonary macrophages in the pathogenesis of pulmonary hypertension (PH). Yet, the molecular mechanisms characterizing the functional macrophage phenotype relative to time and pulmonary localization/compartmentalization remain largely unknown. Here, we utilized a hypoxic murine model of PH in combination with flow cytometry assisted cell sorting (FACS) to quantify and isolate lung macrophages from two compartments over time and characterized their programing via RNA sequencing (RNAseq) approaches. In response to hypoxia, we found an early increase in macrophage number that was restricted to the interstitial/perivascular compartment, without recruitment of macrophages to the alveolar compartment or changes in the number of resident alveolar macrophages. Principle component analysis demonstrated significant differences in overall gene expression between alveolar (AMs) and interstitial macrophages (IMs) at baseline and after 4 and 14 days hypoxic exposure. AM’s at both day 4 and 14 and IM’s at day 4 shared a conserved “hypoxia program” characterized by mitochondrial dysfunction, pro-inflammatory gene activation and mTORC1 signaling, while IM’s at day 14 demonstrated a unique anti-inflammatory/ pro-reparative programming state. We conclude that the pathogenesis of vascular remodeling in hypoxic PH involves an early compartment independent activation of lung macrophages towards a conserved hypoxia program, with the development of compartment specific programs later on in the course of disease. Thus, harnessing time and compartment specific differences in lung macrophage polarization needs to be considered in the therapeutic targeting of macrophages in hypoxic PH and potentially other inflammatory lung diseases.
2017-04-03 | GSE87602 | GEO
Project description:Neutrophil elastase (NE) is implicated in pulmonary arterial hypertension (PAH) but the role of neutrophils in the pathogenesis of PAH is unclear. Here we show that neutrophils from PAH vs. control subjects produce and release increased NE associated with enhanced extracellular trap formation. PAH neutrophils are highly adherent and show decreased migration consistent with increased vinculin, identified on proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic interferon signature in PAH neutrophils and an increase in human endogenous retrovirus (HERV-K) envelope protein. NE and interferon genes are induced by HERV-K envelope and vinculin is increased by HERV-K dUTPase that is elevated in PAH plasma. Neutrophil exosomes from PAH plasma contain increased NE and HERV-K envelope and induce pulmonary hypertension in mice, that is mitigated by the NE inhibitor and antiviral agent, elafin. Thus elevated HERVs explain pathological neutrophils linked to PAH induction and progression.
2023-03-11 | PXD023134 | Pride
Project description:Non-coding RNA plays an important regulatory role in the occurrence and development of hypoxic pulmonary hypertension (HPH). Therefore, we use high-throughput RNA sequence and bioinformatics methods to analyze the whole transcriptome HPH rats in lung tissue.
2021-09-01 | GSE159668 | GEO
Project description:Background: While BMPR2 mutation strongly predisposes to pulmonary arterial hypertension (PAH), only 20% of mutation carriers develop clinical disease. This finding suggests that modifier genes contribute to FPAH clinical expression. Since modifiers are likely to be common alleles, this problem is not tractable by traditional genetic approaches. Further, examination of gene expression is complicated by confounding effects attributable to drugs and the disease process itself. Methods: To resolve these problems, B-cells were isolated, EBV-immortalized, and cultured from familial PAH patients with BMPR2 mutations, mutation positive but disease-free family members, and family members without mutation. This allows examination of differences in gene expression without drug or disease-related effects. These differences were assayed by Affymetrix array, with follow-up by quantitative RT-PCR and additional statistical analyses. Results: By gene array, we found consistent alterations in multiple pathways with known relationship to PAH, including actin organization, immune function, calcium balance, growth, and apoptosis. Selected genes were verified by quantitative RT-PCR using a larger sample set. Analysis of overrepresented gene ontology groups suggests that it is pathway-specific, not gene-specific changes that carry increased risk of disease. Conclusions: B-cell lines are a valuable and accessible tool for assaying alterations in gene expression free from drug and disease effects. Predisposition to disease within BMPR2 mutation carriers was linked to several pathways, including proliferation, GTP signaling, and stress response. Experiment Overall Design: Immortalized B-cells from BMPR2 mutation carriers with and without disease are compared to search for modifier genes
2008-10-25 | E-GEOD-10767 | biostudies-arrayexpress
Project description:Pulmonary Arterial Hypertension (PAH) is a rare disease where the thickening of the precapillary pulmonary arteries ends up inducing right heart failure. Nowadays, getting an early diagnosis is complicated and usually delayed until performing right-heart catheterization. In this work, we performed small RNA sequencing in the plasma of idiopathic PAH patients and controls. We were able to find 29 differentially expressed microRNAs and validate 7 of them in a nationwide cohort (let-7a-5p, let-7b-5p, let-7c-5p, let-7f-5p, miR-9-5p, miR-31-5p, miR-3168). We then used classification models to analyze their potential as PAH predictors. In the first half of our cohort, we obtained a model with an AUC of 0.888. Although, this value lowered to 0.738 after using this model in the whole cohort of patients. Also, we validated the effect of miR-3168, a novel upregulated miRNA in PAH patients that targets the BMPR2 and impairs angiogenesis as measured in tube formation assay. In conclusion, we found novel downregulated and upregulated microRNAs in idiopathic PAH patients. We developed a 3-microRNA signature for diagnosis and validated in vitro that miR-3168 targets BMPR2 and impairs angiogenesis.
2024-03-31 | GSE222022 | GEO
Project description:Whole transcriptome analysis of hypoxic pulmonary hypertension
| PRJNA670164 | ENA
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
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