Effects of ACE2 on BMPR2 mutation-mediated defects in gene expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: James West
PROVIDER: E-GEOD-21583 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:BMPR2 mutation causes pulmonary arterial hypertension (PAH); ACE2 treatment can resolve established BMPR2-mediated PAH. The purpose of this study was to uncover the molecular mechanism behind this.
2010-08-25 | GSE21583 | GEO
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:Pulmonary arterial hypertension (PAH) is thought to be driven by dysfunction of pulmonary vascular microendothelial cells (PMVEC). Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown.
2011-07-01 | GSE28043 | GEO
Project description:Pulmonary arterial hypertension (PAH) is thought to be driven by dysfunction of pulmonary vascular microendothelial cells (PMVEC). Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown. PMVEC were isolated from triple transgenic mice carrying the immortomouse gene, a transactivator, and either control, Bmpr2delx4+ or Bmpr2R899X mutation
2011-07-01 | E-GEOD-28043 | biostudies-arrayexpress
Project description:Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a proliferative endothelial cell phenotype, inflammation and pulmonary vascular remodeling. BMPR2 loss-of-function has been linked to pathologic plexiform lesions with obliteration of distal pulmonary arteries distal pulmonary arteries BMPR2 silencing inprimary human pulmonary artery ECs (HPAECs) recapitulate important aspects of cellular dysfunction and deregulated signaling associated with PAH. Primary HPAECs were transfected with gene-specific siRNA pools targeting BMPR2 or control siRNA followed PMA or control stimulation.
2015-12-04 | E-GEOD-70456 | biostudies-arrayexpress
Project description:Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a proliferative endothelial cell phenotype, inflammation and pulmonary vascular remodeling. BMPR2 loss-of-function has been linked to pathologic plexiform lesions with obliteration of distal pulmonary arteries distal pulmonary arteries BMPR2 silencing inprimary human pulmonary artery ECs (HPAECs) recapitulate important aspects of cellular dysfunction and deregulated signaling associated with PAH.
2015-12-04 | GSE70456 | GEO
Project description:Bmpr2 mutations are critical risk factors for hereditary pulmonary arterial hypertension (hPAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render Bmpr2 mutants susceptible to PAH. Overexpressing 5-lipoxygenase (5-LO) provokes lung inflammation and transient PAH in Bmpr2+/- mice. Accordingly, 5-LO and its metabolite, leukotriene B4 (LTB4), are candidates for the ‘second hit’. The purpose of this study was to determine how 5-LO-mediated pulmonary inflammation synergized with phenotypically-silent Bmpr2 defects to elicit significant pulmonary vascular disease in rats. Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to one year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO-expressing adenovirus (AdAlox5), monocrotaline, SU5416 or chronic hypoxia and analyzed. Bmpr2-mutant hPAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells (PAECs) were cultured with lentivirus expressing short hairpin RNA (shRNA) targeting Bmpr2 (shBmpr2) to model the impaired BMPR2 signaling, and were then exposed to 5-LO-expressing adenovirus (AdAlox5), and were assessed for phenotypic and transcriptomic changes. In vitro, BMPR2 deficiency, compounded by 5-LO-mediated inflammation, generated apoptosis-resistant and proliferative PAECs with mesenchymal characteristics. These transformed cells expressed nuclear envelop-localized 5-LO consistent with induced LTB4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated NF-kB, IL-6 and TGF-β signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 mutants by TGF-β antagonism suggests that TGF-β is critical for neointimal transformation. Thus, in a new two-hit model of disease, lung inflammation induced severe PAH pathology in Bmpr2+/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-β signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced LTB4 production. This study offers one explanation of how an environmental injury unleashes the destructive potential of an otherwise-silent genetic mutation.
2019-07-04 | GSE133749 | GEO
Project description:Upon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.
2021-08-16 | PXD022944 | Pride
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. Keywords: Search for modifier genes
2008-09-01 | GSE10767 | 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