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Paul N. Reynolds - One of the best experts on this subject based on the ideXlab platform.
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BMPR2‐expressing bone marrow‐derived endothelial‐like progenitor cells alleviate pulmonary arterial hypertension in vivo
Respirology (Carlton Vic.), 2019Co-Authors: R. Harper, Suzanne Maiolo, Rebekah J. Ward, Jemma Seyfang, Michaelia P. Cockshell, Claudine S. Bonder, Paul N. ReynoldsAbstract:Background and objective Pulmonary arterial hypertension (PAH) is characterized by increased resistance in the distal pulmonary arteries, ultimately leading to right heart failure and, despite the available therapeutics, survival remains poor. Reduced expression of bone morphogenetic protein receptor type 2 (BMPR2) is strongly associated with PAH. Cell therapies are of interest in PAH, but whether this approach can upregulate BMPR2 is not known. Our objective was to evaluate a preclinical cell therapy approach based on upregulation of BMPR2. Methods We assessed the therapeutic effect of intravenously injected BMPR2-augmented rat bone marrow-derived endothelial-like progenitor cells (BMPR2-BM-ELPC) on PAH in the rat monocrotaline (MCT) model. Results The cells accumulate in the lungs with negligible systemic distribution, but the vast majority are lost from the lungs by 24 h. Lungs from rats treated with BMPR2-BM-ELPC exhibited an immediate increase in BMPR2 and related intracellular signalling proteins. Treatment with BMPR2-BM-ELPC attenuated PAH as demonstrated by a reduction in right ventricular hypertrophy as well as right ventricular systolic and mean pulmonary arterial pressures. In addition, this treatment reversed PAH-induced vascular remodelling with a significant reduction in vessel thickness and muscularization. In view of the short retention time of injected cells in the lungs, the mechanism for the effects seen may be intracellular communication via exosomes. In support of this hypothesis, we demonstrate that BMPR2-transduced outgrowth endothelial progenitor cells (OECs) release BMPR2-expressing exosomes. Conclusion BMPR2-augmented ELPC demonstrate therapeutic benefits in the rat model and may have clinical translation potential.
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Vascular remodelling is reversed following BMPR2 modified endothelial progenitor cell therapy in a MCT-induced PAH rat model
4.3 Pulmonary Circulation and Pulmonary Vascular Diseases, 2016Co-Authors: R. Harper, Rebekah J. Ward, Claudine S. Bonder, Paul N. ReynoldsAbstract:Introduction: Pulmonary arterial hypertension (PAH) is caused by pulmonary vascular remodelling. Reduced expression of the bone morphogenetic protein receptor type-2 (BMPR2) is causally linked to PAH. Previously, we have augmented endothelial progenitor cells (EPCs) to over-express BMPR2 and transplanted them in a monocrotaline (MCT)-induced PAH rat model resulting in an amelioration of the disease. We now assess the effects of our BMPR2-EPC and EPC only therapy on vascular remodelling in this MCT-induced PAH rat model. Method: Rats (n=8) were injected with MCT, and then at day 10, rats were intravenously injected with EPCs only, AdBMPR2 transfected EPCs, or uninjected. After a further 8-10 days, PAH was assessed and lungs were extracted and processed into paraffin blocs. Immunohistochemical analysis on vessels 50µm or less was performed with α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA). Results: After 8-10 days PAH was shown to be attenuated in the BMPR2-transduced EPC group, with a reduction in the mPAP of the EPCs Only group compared to MCT Only. Rats treated with EPCs Only had a significant reduction by 30.47% in vessel muscularisation and 39.59% reduction in cellular proliferation compared to MCT Only. Rats treated with BMPR2-EPCs had a 31.21% reduction in vessel muscularisation and a 52.97% reduction in cellular proliferation compared to MCT Only treated rats. Discussion: Amelioration of PAH can be achieved using BMPR2 modified EPCs. There9s a significant reduction in distal vessel muscularisation and cellular proliferation following EPCs and BMPR2-EPCs treatment, with a greater effect seen in the BMPR2-EPCs group.
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BMPR2 gene therapy for pah acts via smad and non smad signalling
Respirology, 2016Co-Authors: R. Harper, Claudine S. Bonder, Paul N. Reynolds, Ann M. ReynoldsAbstract:Background and objective Pulmonary arterial hypertension (PAH) continues to be a fatal disease and is associated with downregulation of bone morphogenetic protein receptor type-2 (BMPR2). Our approach is to upregulate BMPR2 in the pulmonary vasculature allowing us to examine the changes in endothelial cell signalling and better understand what pathways are altered when disease is attenuated using this treatment approach. Methods We used gene delivery of BMPR2 to human pulmonary endothelial cells to investigate downstream signalling, then assessed the impact of this approach on downstream signalling in vivo in rats with PAH using the monocrotaline (MCT) model. Results Gene delivery of BMPR2 leads to an increase in BMPR2 protein expression, and this is associated with increased Smad1/5/8 and reduced Smad2/3 signalling. Additionally, we have found that BMPR2 modulation has effects on non-Smad signalling with increases found in phosphoinositide-3 kinase (PI3K) and a decrease in phosphorylated-p38-mitogen activated protein kinase (p38-MAPK) in vivo. These findings are associated with amelioration of PAH (reduced right ventricular, mean pulmonary artery pressures and Fulton Index). Conclusion These results indicate that the therapeutic effect of BMPR2 gene delivery on PAH is associated with a switch between TGF-β-Smad2/3 signalling to BMPR2-Smad1/5/8 signalling. This supports the further development of this treatment approach.
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BMPR2 gene therapy for PAH acts via Smad and non‐Smad signalling
Respirology (Carlton Vic.), 2016Co-Authors: R. Harper, Claudine S. Bonder, Ann M. Reynolds, Paul N. ReynoldsAbstract:Background and objective Pulmonary arterial hypertension (PAH) continues to be a fatal disease and is associated with downregulation of bone morphogenetic protein receptor type-2 (BMPR2). Our approach is to upregulate BMPR2 in the pulmonary vasculature allowing us to examine the changes in endothelial cell signalling and better understand what pathways are altered when disease is attenuated using this treatment approach. Methods We used gene delivery of BMPR2 to human pulmonary endothelial cells to investigate downstream signalling, then assessed the impact of this approach on downstream signalling in vivo in rats with PAH using the monocrotaline (MCT) model. Results Gene delivery of BMPR2 leads to an increase in BMPR2 protein expression, and this is associated with increased Smad1/5/8 and reduced Smad2/3 signalling. Additionally, we have found that BMPR2 modulation has effects on non-Smad signalling with increases found in phosphoinositide-3 kinase (PI3K) and a decrease in phosphorylated-p38-mitogen activated protein kinase (p38-MAPK) in vivo. These findings are associated with amelioration of PAH (reduced right ventricular, mean pulmonary artery pressures and Fulton Index). Conclusion These results indicate that the therapeutic effect of BMPR2 gene delivery on PAH is associated with a switch between TGF-β-Smad2/3 signalling to BMPR2-Smad1/5/8 signalling. This supports the further development of this treatment approach.
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BMPR2 gene delivery reduces mutation related pah and counteracts tgf β mediated pulmonary cell signalling
Respirology, 2016Co-Authors: Feng Feng, R. Harper, Paul N. ReynoldsAbstract:Background and objective Idiopathic, familial and secondary pulmonary arterial hypertension (PAH) are associated with reduced bone morphogenetic protein receptor type 2 (BMPR2) expression, and in some contexts, TGF-β upregulation. Our aims were to assess BMPR2 gene therapy in a PAH mouse model and to assess the impact on TGF-β signalling. Methods Using a targeted in vivo gene delivery approach, we assessed the impact of BMPR2 gene delivery in a transgenic mouse model in which PAH was first induced by doxycycline driven expression of a dominant negative BMPR2 mutant (R899X). We also assessed the impact of BMPR2 gene delivery on TGF-β-induced changes in cell signalling in human pulmonary vascular endothelial and smooth muscle cells. Results In the mouse model, changes in TGF-β levels were not detected, but BMPR2 gene delivery reversed the increase in right ventricle systolic pressure (RVSP) and Fulton Index (FI), associated with a trend to increased pulmonary endothelial nitric oxide synthase (eNOS) gene expression. In vitro, BMPR2 gene transfer reduced TGF-β effects on Smad2, Smad1/5/8 and Erk1/2 phosphorylation in human pulmonary arterial smooth muscle cells (HPASMC). BMPR2 was also found to upregulate nitric oxide (NO) production in lung derived human microvascular endothelial cells (HMVEC-L). Conclusion This study provides further evidence that BMPR2 modulation may have therapeutic potential.
R. Harper - One of the best experts on this subject based on the ideXlab platform.
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BMPR2‐expressing bone marrow‐derived endothelial‐like progenitor cells alleviate pulmonary arterial hypertension in vivo
Respirology (Carlton Vic.), 2019Co-Authors: R. Harper, Suzanne Maiolo, Rebekah J. Ward, Jemma Seyfang, Michaelia P. Cockshell, Claudine S. Bonder, Paul N. ReynoldsAbstract:Background and objective Pulmonary arterial hypertension (PAH) is characterized by increased resistance in the distal pulmonary arteries, ultimately leading to right heart failure and, despite the available therapeutics, survival remains poor. Reduced expression of bone morphogenetic protein receptor type 2 (BMPR2) is strongly associated with PAH. Cell therapies are of interest in PAH, but whether this approach can upregulate BMPR2 is not known. Our objective was to evaluate a preclinical cell therapy approach based on upregulation of BMPR2. Methods We assessed the therapeutic effect of intravenously injected BMPR2-augmented rat bone marrow-derived endothelial-like progenitor cells (BMPR2-BM-ELPC) on PAH in the rat monocrotaline (MCT) model. Results The cells accumulate in the lungs with negligible systemic distribution, but the vast majority are lost from the lungs by 24 h. Lungs from rats treated with BMPR2-BM-ELPC exhibited an immediate increase in BMPR2 and related intracellular signalling proteins. Treatment with BMPR2-BM-ELPC attenuated PAH as demonstrated by a reduction in right ventricular hypertrophy as well as right ventricular systolic and mean pulmonary arterial pressures. In addition, this treatment reversed PAH-induced vascular remodelling with a significant reduction in vessel thickness and muscularization. In view of the short retention time of injected cells in the lungs, the mechanism for the effects seen may be intracellular communication via exosomes. In support of this hypothesis, we demonstrate that BMPR2-transduced outgrowth endothelial progenitor cells (OECs) release BMPR2-expressing exosomes. Conclusion BMPR2-augmented ELPC demonstrate therapeutic benefits in the rat model and may have clinical translation potential.
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Vascular remodelling is reversed following BMPR2 modified endothelial progenitor cell therapy in a MCT-induced PAH rat model
4.3 Pulmonary Circulation and Pulmonary Vascular Diseases, 2016Co-Authors: R. Harper, Rebekah J. Ward, Claudine S. Bonder, Paul N. ReynoldsAbstract:Introduction: Pulmonary arterial hypertension (PAH) is caused by pulmonary vascular remodelling. Reduced expression of the bone morphogenetic protein receptor type-2 (BMPR2) is causally linked to PAH. Previously, we have augmented endothelial progenitor cells (EPCs) to over-express BMPR2 and transplanted them in a monocrotaline (MCT)-induced PAH rat model resulting in an amelioration of the disease. We now assess the effects of our BMPR2-EPC and EPC only therapy on vascular remodelling in this MCT-induced PAH rat model. Method: Rats (n=8) were injected with MCT, and then at day 10, rats were intravenously injected with EPCs only, AdBMPR2 transfected EPCs, or uninjected. After a further 8-10 days, PAH was assessed and lungs were extracted and processed into paraffin blocs. Immunohistochemical analysis on vessels 50µm or less was performed with α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA). Results: After 8-10 days PAH was shown to be attenuated in the BMPR2-transduced EPC group, with a reduction in the mPAP of the EPCs Only group compared to MCT Only. Rats treated with EPCs Only had a significant reduction by 30.47% in vessel muscularisation and 39.59% reduction in cellular proliferation compared to MCT Only. Rats treated with BMPR2-EPCs had a 31.21% reduction in vessel muscularisation and a 52.97% reduction in cellular proliferation compared to MCT Only treated rats. Discussion: Amelioration of PAH can be achieved using BMPR2 modified EPCs. There9s a significant reduction in distal vessel muscularisation and cellular proliferation following EPCs and BMPR2-EPCs treatment, with a greater effect seen in the BMPR2-EPCs group.
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BMPR2 gene therapy for pah acts via smad and non smad signalling
Respirology, 2016Co-Authors: R. Harper, Claudine S. Bonder, Paul N. Reynolds, Ann M. ReynoldsAbstract:Background and objective Pulmonary arterial hypertension (PAH) continues to be a fatal disease and is associated with downregulation of bone morphogenetic protein receptor type-2 (BMPR2). Our approach is to upregulate BMPR2 in the pulmonary vasculature allowing us to examine the changes in endothelial cell signalling and better understand what pathways are altered when disease is attenuated using this treatment approach. Methods We used gene delivery of BMPR2 to human pulmonary endothelial cells to investigate downstream signalling, then assessed the impact of this approach on downstream signalling in vivo in rats with PAH using the monocrotaline (MCT) model. Results Gene delivery of BMPR2 leads to an increase in BMPR2 protein expression, and this is associated with increased Smad1/5/8 and reduced Smad2/3 signalling. Additionally, we have found that BMPR2 modulation has effects on non-Smad signalling with increases found in phosphoinositide-3 kinase (PI3K) and a decrease in phosphorylated-p38-mitogen activated protein kinase (p38-MAPK) in vivo. These findings are associated with amelioration of PAH (reduced right ventricular, mean pulmonary artery pressures and Fulton Index). Conclusion These results indicate that the therapeutic effect of BMPR2 gene delivery on PAH is associated with a switch between TGF-β-Smad2/3 signalling to BMPR2-Smad1/5/8 signalling. This supports the further development of this treatment approach.
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BMPR2 gene therapy for PAH acts via Smad and non‐Smad signalling
Respirology (Carlton Vic.), 2016Co-Authors: R. Harper, Claudine S. Bonder, Ann M. Reynolds, Paul N. ReynoldsAbstract:Background and objective Pulmonary arterial hypertension (PAH) continues to be a fatal disease and is associated with downregulation of bone morphogenetic protein receptor type-2 (BMPR2). Our approach is to upregulate BMPR2 in the pulmonary vasculature allowing us to examine the changes in endothelial cell signalling and better understand what pathways are altered when disease is attenuated using this treatment approach. Methods We used gene delivery of BMPR2 to human pulmonary endothelial cells to investigate downstream signalling, then assessed the impact of this approach on downstream signalling in vivo in rats with PAH using the monocrotaline (MCT) model. Results Gene delivery of BMPR2 leads to an increase in BMPR2 protein expression, and this is associated with increased Smad1/5/8 and reduced Smad2/3 signalling. Additionally, we have found that BMPR2 modulation has effects on non-Smad signalling with increases found in phosphoinositide-3 kinase (PI3K) and a decrease in phosphorylated-p38-mitogen activated protein kinase (p38-MAPK) in vivo. These findings are associated with amelioration of PAH (reduced right ventricular, mean pulmonary artery pressures and Fulton Index). Conclusion These results indicate that the therapeutic effect of BMPR2 gene delivery on PAH is associated with a switch between TGF-β-Smad2/3 signalling to BMPR2-Smad1/5/8 signalling. This supports the further development of this treatment approach.
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BMPR2 gene delivery reduces mutation related pah and counteracts tgf β mediated pulmonary cell signalling
Respirology, 2016Co-Authors: Feng Feng, R. Harper, Paul N. ReynoldsAbstract:Background and objective Idiopathic, familial and secondary pulmonary arterial hypertension (PAH) are associated with reduced bone morphogenetic protein receptor type 2 (BMPR2) expression, and in some contexts, TGF-β upregulation. Our aims were to assess BMPR2 gene therapy in a PAH mouse model and to assess the impact on TGF-β signalling. Methods Using a targeted in vivo gene delivery approach, we assessed the impact of BMPR2 gene delivery in a transgenic mouse model in which PAH was first induced by doxycycline driven expression of a dominant negative BMPR2 mutant (R899X). We also assessed the impact of BMPR2 gene delivery on TGF-β-induced changes in cell signalling in human pulmonary vascular endothelial and smooth muscle cells. Results In the mouse model, changes in TGF-β levels were not detected, but BMPR2 gene delivery reversed the increase in right ventricle systolic pressure (RVSP) and Fulton Index (FI), associated with a trend to increased pulmonary endothelial nitric oxide synthase (eNOS) gene expression. In vitro, BMPR2 gene transfer reduced TGF-β effects on Smad2, Smad1/5/8 and Erk1/2 phosphorylation in human pulmonary arterial smooth muscle cells (HPASMC). BMPR2 was also found to upregulate nitric oxide (NO) production in lung derived human microvascular endothelial cells (HMVEC-L). Conclusion This study provides further evidence that BMPR2 modulation may have therapeutic potential.
Nicholas W. Morrell - One of the best experts on this subject based on the ideXlab platform.
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Haploid genetic screening identifies a novel regulator of BMPR2
Pulmonary hypertension, 2020Co-Authors: Benjamin J. Dunmore, Stephen P. Burr, Paul D. Upton, James A. Nathan, Nicholas W. MorrellAbstract:Pulmonary arterial hypertension (PAH), is characterised by profound remodelling of small pulmonary arteries, leading to increased pulmonary arterial pressures and premature death by right heart failure. Heterozygous germ-line mutations in the bone morphogenetic protein type II receptor (BMPR2) cause ~70% of familial PAH and ~20% of idiopathic PAH cases. The majority of mutations lead to haploinsufficiency but crucially, regardless of the presence of mutation, lung BMPR2 expression is reduced in all forms of PAH. Therefore, restoration of BMPR2 levels is an important therapeutic target. We previously showed that BMPR2 ubiquitination results in lysosomal degradation and can be partially inhibited by the lysosomotropic drug, chloroquine. However, the factors involved in regulating BMPR2 turnover remain poorly understood. We employed a haploid forward genetic screen to identify potential targets involved in controlling BMPR2 expression. Next-generation sequencing identified ~800 “inactivated” genes that induced “high” BMPR2 expression. Novel genes were selected based upon functional relevance in lysosomal degradation or ubiquitination, including the E2 ligase, UBE2E2. UBE2E2 knockdown in pulmonary artery endothelial cells significantly increased BMPR2 protein expression and reduced proliferation and apoptosis. Also, downstream signalling was enhanced in UBE2E2 siRNA targeted cells with phospho-Smad1/5 and ID2 increased in pulmonary endothelial cells. Moreover, UBE2E2 was highly expressed in remodelled vascular lesions in lungs of PAH patients. These observations highlight a new approach to the discovery of novel pathways regulating BMPR2 protein expression which might lead to the discovery of novel therapeutics in PAH.
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S82 Bone marrow transplantation reduces susceptibility to pulmonary hypertension in BMPR2 deficient mice
Thorax, 2016Co-Authors: Alexi Crosby, Mark Southwood, Elaine Soon, Mark Toshner, Benjamin J. Dunmore, Nicholas W. MorrellAbstract:Introduction Increasing evidence suggests that patients with pulmonary arterial hypertension (PAH) have abnormalities in the bone marrow (BM). Approximately 40% of patients with PAH are reported to have evidence of myelodysplasia. Conversely PAH is often found (13–48%) in patients with myeloproliferative disease. In a bone marrow transplant (BMT) model it has been shown that mice transplanted with CD133+ cells from PAH patients developed pulmonary vascular remodelling and right ventricular hypertrophy; whereas, CD133+ cells from controls did not. CD133+ cells from PAH patients also showed greater myeloid commitment. Since mutation in the bone morphogenetic protein receptor type 2 (BMPR2) is the commonest genetic cause of PAH we questioned whether bone marrow transplantation of wild type bone marrow reduces the susceptibility to PAH in the BMPR2 heterozygous mouse. Methods WT mice were transplanted with BMPR2 ± BM and BMPR2 ± mice were transplanted with WT BM. Sixteen weeks post-transplant mice were exposed to low-dose chronic LPS (0.5 mg/kg 3 times a week for 6 weeks), which we recently showed is a potent stimulus for the development of PAH in the BMPR2 heterozygous mouse. Mice underwent right heart catheterisation. Tissues were removed for histology. Results We observed a significant increase in RVSP when WT mice were transplanted with BMPR2 ± bone marrow after chronic LPS dosing. There was an increase in spleen weight and circulating platelets in WT mice with BMPR2 ± bone marrow and a converse reduction in spleen weight and platelets in BMPR2 ± mice with WT BM. Bone marrow histology demonstrated reduced myeloid cells and megakaryocytes, iron deposition and fibrosis related to LPS administration. In preventative studies BMPR2 ± mice transplanted with WT bone marrow did not develop significant pulmonary hypertension after chronic LPS exposure. Conclusions The susceptibility to PAH in the BMPR2 heterozygous mouse can be conferred on a wild type animal by bone marrow transplantation of BMPR2 deficient bone marrow. Transplanting WT BM into BMPR2 ± mice prevented PAH. The role of bone marrow derived cells in the pathobiology of PAH requires further elucidation, but may point to a potential future treatment
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Correction of Nonsense BMPR2 and SMAD9 Mutations by Ataluren in Pulmonary Arterial Hypertension
American journal of respiratory cell and molecular biology, 2013Co-Authors: Kylie M. Drake, Nicholas W. Morrell, Benjamin J. Dunmore, Lauren N. Mcnelly, Micheala A. AldredAbstract:Heritable pulmonary arterial hypertension (HPAH) is a serious lung vascular disease caused by heterozygous mutations in the bone morphogenetic protein (BMP) pathway genes, BMPR2 and SMAD9. One noncanonical function of BMP signaling regulates biogenesis of a subset of microRNAs. We have previously shown that this function is abrogated in patients with HPAH, making it a highly sensitive readout of BMP pathway integrity. Ataluren (PTC124) is an investigational drug that permits ribosomal readthrough of premature stop codons, resulting in a full-length protein. It exhibits oral bioavailability and limited toxicity in human trials. Here, we tested ataluren in lung- or blood-derived cells from patients with HPAH with nonsense mutations in BMPR2 (n = 6) or SMAD9 (n = 1). Ataluren significantly increased BMP-mediated microRNA processing in six of the seven cases. Moreover, rescue was achieved even for mutations exhibiting significant nonsense-mediated mRNA decay. Response to ataluren was dose dependent, and complete correction was achieved at therapeutic doses currently used in clinical trials for cystic fibrosis. BMP receptor (BMPR)-II protein levels were normalized and ligand-dependent phosphorylation of downstream target Smads was increased. Furthermore, the usually hyperproliferative phenotype of pulmonary artery endothelial and smooth muscle cells was reversed by ataluren. These results indicate that ataluren can effectively suppress a high proportion of BMPR2 and SMAD9 nonsense mutations and correct BMP signaling in vitro. Approximately 29% of all HPAH mutations are nonsense point mutations. In light of this, we propose ataluren as a potential new personalized therapy for this significant subgroup of patients with PAH.
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abstract 16942 effects of BMPR2 mutations on global microrna expression profiles in blood outgrowth endothelial cells from patients with pulmonary arterial hypertension
Circulation, 2012Co-Authors: Kenny Schlosser, Nicholas W. Morrell, Mark L Ormiston, Duncan StewartAbstract:Background: Mutations of the bone morphogenetic protein receptor 2 gene ( BMPR2 ) are found in patients with heritable (H) or idiopathic (I) pulmonary arterial hypertension (PAH). However, their role in abnormalities of endothelial cell (EC) growth and survival in PAH is unclear. Therefore, blood-outgrowth endothelial cells (BOECs), which closely resemble mature endothelial cells, were used to study patient-specific effects of BMPR2 mutations on endothelial microRNAs (miRNA), which are recognized to be key regulators of gene expression. Hypothesis: Disease-specific alterations in miRNA expression profiles in BOECs from patients with HPAH or IPAH, with and without BMPR2 mutations, contribute to the previously reported abnormalities in EC growth and survival in this disease. Methods: BOECs were derived from the peripheral blood mononuclear cell fraction isolated from 7 patients (4 HPAH with BMPR2 mutations, and 3 IPAH) and 5 healthy controls (including 1 unaffected BMPR2 mutation carrier). Cells were characterized by cobblestone morphology and surface marker profile (cd31+/cd45-/cd14-/cd34+/KDR+). 1066 miRNAs were measured using an (RT)-qPCR array platform (Qiagen), and normalized with a mean-centering restricted method. Results: 767 ± 30 miRNAs were detected in BOECs from the 12 participants (PCR Cq cutoff BMPR2 mutations vs. controls (p BMPR2 mutation carrier. Conclusion: A global analysis of miRNAs in BOECs revealed distinct profiles in IPAH and HPAH patients, with both disease- and BMPR2 mutation-specific patterns of expression. These data suggest that unique miRNAs may contribute to alterations in endothelial gene expression that underlie abnormalities in EC growth and survival, and may be novel targets for therapeutic and biomarker development.
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P139 Survival of Idiopathic Pulmonary Arterial Hypertension BMPR2 Mutation Carriers Vs BMPR2 Non Carriers
Thorax, 2012Co-Authors: Carmen M. Treacy, Nicholas W. Morrell, D Taboada Buasso, N Doughty, Joanna Pepke-zabaAbstract:Introduction Idiopathic pulmonary arterial hypertension (IPAH) is a devastating condition charactericed by the narrowing and obliteration of small pulmonary arteries, leading to elevated pulmonary arterial pressure and ultimately to right heart failure and death. Even with treatment, IPAH survival is poor with 3 year survival reported to be 63% on epoprostenol (Mclaughlin, Circulation 2002). Pulmonary arterial hypertension (PAH) can be heritable, with mutations found in the bone morphogenetic protein type 2 receptor (BMPR2) gene found in > 70% of familial cases, (Lane, Nat Genet 2000). There are previous conflicting reports of worse survival in heritable PAH, but this has not previously been determined in the UK patient population. Methods This study examined the retrospective database of 76 IPAH cases diagnosed between 2001–2006. 32 patients were screened for BMPR2 mutation. 13 were BMPR2+ve. Non-screened (NS) IPAH were included in the survival analysis (n=44). Survival time was taken from the time of initial diagnostic right heart catherisation. Demographics, treatment, 6MWT, time to transplant and World Health Organization (WHO) classification were compared. Physicians were blinded to the BMPR2 status at time of treatment. Results All three cohorts presented at baseline with no significant difference in functional class, 6MWT, hemodynamics except age, cardiac index (CI), right atrial pressure (RAP) and treatment modalities. Patients with BMPR2 mutation were significantly younger. Of the BMPR+ve group, 6 patients were transplanted compared to zero in the BMPR-ve group. The NS IPAH cohort had 2 patients transplanted and fewer patients were treated with prostanoids. Time to transplant was shorter in the BMPR2 mutation carriers, 2.65 years, vs. 3.1years in the NS IPAH group. Conclusion Survival for the first 5 years from diagnosis was similar in IPAH and heritable PAH. The BMPR2 +ve patients presented younger with severe disease and were treated more aggressively with 6 patients undergoing transplant in the 5 year period. BMPR2 mutation frequency was 41% from our cohort of 33 which is higher than previously reports of 20–30% (Morrell, Proc Am Thorac Soc, 2006). Survival for IPAH continues to be poor even with improvements in treatment. Patients with BMPR2 mutations present with severe disease earlier and time to lung transplant is shorter.
Zhi-cheng Jing - One of the best experts on this subject based on the ideXlab platform.
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BMPR2 mutation is a potential predisposing genetic risk factor for congenital heart disease associated pulmonary vascular disease
International Journal of Cardiology, 2016Co-Authors: Xin Jiang, Dong Liu, Zhi-cheng Jing, Qianqian Liu, Lihua Guan, Daxin Zhou, Maurice BeghettiAbstract:Abstract Background Pulmonary arterial hypertension (PAH) frequently arises in patients with congenital heart disease (CHD) and can lead to pulmonary vascular disease (PVD). The present study was initiated to distinguish the predisposing effect of bone morphogenetic protein receptor 2 ( BMPR2 ) in CHD by comparing the different mutation features of BMPR2 between CHD patients with or without PVD. Methods and results 294 CHD–PVD and 161 CHD without PVD patients were enrolled. PAH was diagnosed by heart catheterization at rest after CHD was first recognized by echocardiography. PVD was defined as a pulmonary vascular resistance (PVR) more than 3Wood units. BMPR2 gene was screened by direct sequencing. A total of 24 mutations were identified, accounting for 22 of the 294 patients with CHD–PVD (7.5%) and 2 of the 161 CHD patients without PVD (1.2%, P =0.004). Female/male CHD–PVD patient ratio was 1.6:1, while in the BMPR2 mutation carriers female patients were more dominant (4.5:1, P =0.042). A significant higher BMPR2 mutation rate (12.6%) was found in repaired CHD–PVD ( P =0.010). BMPR2 mutations in CHD–PVD patients were identified in different clinical phenotypes. Missense mutation of BMPR2 is the dominant mutation type. Conclusion Genetic predisposing factor may be an important component in the process of development of PVD in CHD patients. Female, repaired patients are more likely to be detected with genetic mutations.
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BMPR2 Germline Mutation in Chronic Thromboembolic Pulmonary Hypertension
Lung, 2014Co-Authors: Yu-xuan Feng, Xin Jiang, Dong Liu, Ming-li Sun, Na Sun, Yi-min Mao, Zhi-cheng JingAbstract:Introduction Heterozygous germline mutations of the bone morphogenetic protein type II receptor (BMPR2) gene BMPR2 are the most important predisposing factors for heritable pulmonary arterial hypertension. BMPR2 mutation was occasionally reported in pulmonary veno-occlusive disease, appetite suppressant-related pulmonary arterial hypertension (PAH), and PAH with congenital heart disease.
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BMPR2 Mutations Influence Phenotype More Obviously in Male Patients with Pulmonary Arterial Hypertension
Circulation. Cardiovascular genetics, 2012Co-Authors: Dong Liu, Yi-min Mao, Ping Yuan, Rui Zhang, Zhi-cheng JingAbstract:Background— BMPR2 mutations predispose to idiopathic and heritable pulmonary arterial hypertension (IPAH and HPAH). The influence of BMPR2 mutations on clinical outcome is not concordant in different ethnic groups. Although the BMPR2 mutation spectrum and mutation rate in Chinese PAH patients has been reported previously, the influence of genotype on phenotype and whether this influence is associated with sex have not been investigated. Methods and Results— We analyzed data from 305 PAH patients considered as either idiopathic or heritable who underwent genetic counseling in Shanghai Pulmonary Hospital. The clinical, functional, and hemodynamic characteristics of BMPR2 mutation carriers and noncarriers were compared. The more severe hemodynamic compromise at diagnosis in BMPR2 mutation carriers versus noncarriers is concordant with other ethnic groups. In the Chinese PAH cohort, BMPR2 mutations were associated with a higher risk of mortality after adjustment for age and sex (hazard ratio, 1.971; 95% confidence interval, 1.121–3.466; P =0.018). The overall survival difference between mutation carriers and noncarriers was more obvious in male patients, which was reflected by a higher mortality risk of male mutation carriers than that of male noncarriers after adjustment for age at diagnosis (hazard ratio, 3.702; 95% confidence interval, 1.416–9.679; P =0.008). In females, this trend did not reach statistical significance. Conclusions— BMPR2 mutations influence phenotype more obviously in male PAH patients. The pathogenesis of female PAH patients is more complicated, and the influence of BMPR2 mutations may be modified by other unknown factors, making disparities in the prognosis between female mutation carriers and noncarriers less evident.
Marc Humbert - One of the best experts on this subject based on the ideXlab platform.
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nmda receptor crosstalk with pdgfr β and BMPR2 is involved in smooth muscle cell proliferation in pulmonary arterial hypertension
European Respiratory Journal, 2016Co-Authors: Marc Humbert, Marceau Quatredeniers, Audrey Courboulin, Sebastien J Dumas, N Doisne, Sylvia CohenkaminskyAbstract:Pulmonary Arterial Hypertension (PAH) is due to remodeling and obstruction of small pulmonary vessels, leading to right heart hypertrophy and death. Remodeling involves smooth muscle cells (SMCs) overproliferation. We have previously shown that NMDA receptor (NMDAR) is expressed by pulmonary SMCs and contributes to their proliferation in PAH. In neurons, Src has been described as a hub for signaling pathways enhancing NMDAR activity. Besides in PAH, Src is known to dysregulate vascular processes, especially vascular cell proliferation. Src has been identified as a binding partner of the C-terminus of BMPR2 (Wong, W.K. et al. AJRCMB. 2005), a protein encoded by the BMPR2 gene which is the main genetic factor of susceptibility in PAH. In addition, Src activity is enhanced by PDGFR-β signaling which is increased in PAH (Perros, F. et al. AJRCCM. 2008). We hypothesized that both BMPR2 impaired signaling and PDGFR-βoveractivation lead to increased Src activationin PAH, thus enhancing the NMDAR activity and leading to SMCs proliferation. Phosphorylation levels were assessed by western blot in explanted lungs of PAH patients and in pulmonary arterial SMCs. Interaction between different partners was studied by immunoprecipitation and immunostainings. We demonstrate that PAH patients show increased Src and NMDAR subunits (GluN2) phosphorylation. BMP2 stimulation decreases Src and GluN2B activation, whereas PDGF stimulation enhances Src, GluN2A and GluN2B phosphorylations in a time-dependent manner, possibly promoting NMDAR subunits trafficking. Thus vascular remodeling in PAH could involve BMPR2-PDGFR-β-NMDAR crosstalk through Src mobilization.
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Diffusion capacity and BMPR2 mutations in pulmonary arterial hypertension.
The European respiratory journal, 2013Co-Authors: Pia Trip, Marc Humbert, Barbara Girerd, David Montani, Herman J. Bogaard, F.s. De Man, Anco Boonstra, Gilles Garcia, Anton Vonk-noordegraafAbstract:To the Editor: Pulmonary arterial hypertension (PAH) is a disease in which remodelling of the small pulmonary arteries leads to an increase in pulmonary artery pressure (PAP). The most important genetic predisposing factor related to PAH is a mutation in the bone morphogenetic protein receptor type 2 gene ( BMPR2 ) [1, 2]. BMPR2 mutation carriers are known to present with disease at an earlier age and with worse haemodynamics [3]. We recently showed in a cohort of patients with idiopathic and hereditary PAH that a very low diffusion capacity for carbon monoxide ( D LCO) is exclusively found in some of the patients without identified BMPR2 mutations, whereas BMPR2 mutation carriers have a relatively preserved D LCO [4]. D LCO is a noninvasive marker of the quality of the alveolar capillary structure [5] and the observed difference in D LCO supports the hypothesis that distinct vascular disease processes are at play in BMPR2 mutation-related PAH and non BMPR2 mutation-related idiopathic PAH. Until recently, insufficient availability of lung samples has prohibited the performance of a detailed comparison of the pulmonary vascular pathologies in these two disease groups [6]. Therefore, we sought, in the present study, to confirm the previously found influence of BMPR2 mutations on diffusion capacity in a much larger multinational patient cohort. We performed a retrospective collaborative study at the VU University Medical Center in Amsterdam, the Netherlands and the Universite Paris-Sud, Assistance Publique Hopitaux de Paris, Le Kremlin-Bicetre, France. Patients were eligible for this study when classified in the database with idiopathic or familial PAH, and when the results from BMPR2 mutation analysis and D LCO measurements were available. Patients were diagnosed with idiopathic …
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Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension.
Respiratory Research, 2010Co-Authors: Barbara Girerd, Gérald Simonneau, Olivier Sitbon, David Montani, Mélanie Eyries, Azzedine Yaici, Benjamin Sztrymf, Florence Coulet, Florent Soubrier, Marc HumbertAbstract:BACKGROUND: Previous studies indicate that patients with pulmonary arterial hypertension (PAH) carrying a mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene, develop the disease 10 years earlier than non-carriers, and have a more severe hemodynamic compromise at diagnosis. A recent report has suggested that this may only be the case for females and that patients with missense mutations in BMPR2 gene have more severe disease than patients with truncating mutations. METHODS: We reviewed data from all patients with PAH considered as idiopathic and patients with a family history of PAH, who underwent genetic counselling in the French PAH network between January, 1st 2004 and April, 1st 2010. We compared clinical, functional, and hemodynamic characteristics between carriers and non-carriers of a BMPR2 mutation, according to gender or BMPR2 mutation type. RESULTS: PAH patients carrying a BMPR2 mutation (n = 115) were significantly younger at diagnosis than non-carriers (n = 267) (35.8 +/- 15.4 and 47.5 +/- 16.2 respectively, p < 0.0001). The presence of a BMPR2 mutation was associated with a younger age at diagnosis in females (36.4 +/- 14.9 in BMPR2 mutation carriers and 47.4 +/- 15.8 in non-carriers, p < 0.0001), and males (34.6 +/- 16.8 in BMPR2 mutation carriers and 47.8 +/- 17.1 in non-carriers, p < 0.0001). BMPR2 mutation carriers had a more severe hemodynamic compromise at diagnosis, but this was not influenced by gender. No differences in survival and time to death or lung transplantation were found in male and female PAH patients carrying a BMPR2 mutation. No differences were observed in clinical outcomes according to the type of BMPR2 mutations (missense, truncating, large rearrangement or splice defect). CONCLUSION: When compared to non-carriers, BMPR2 mutation carriers from the French PAH network are younger at diagnosis and present with a more severe hemodynamic compromise, irrespective of gender. Moreover, BMPR2 mutation type had no influence on clinical phenotypes in our patient population.
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BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives
The European respiratory journal, 2002Co-Authors: Marc Humbert, Z. Deng, Gérald Simonneau, Robyn J. Barst, Olivier Sitbon, Martine Wolf, Nieves Cuervo, K.j. Moore, Susan E. Hodge, James A. KnowlesAbstract:This study investigated whether patients developing pulmonary arterial hypertension (PAH) after exposure to the appetite suppressants fenfluramine and dexfenfluramine have mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, as reported in primary pulmonary hypertension. BMPR2 was examined for mutations in 33 unrelated patients with sporadic PAH, and in two sisters with PAH, all of whom had taken fenfluramine derivatives, as well as in 130 normal controls. The PAH patients also underwent cardiac catheterisation and body mass determinations. Three BMPR2 mutations predicting changes in the primary structure of the BMPR-II protein were found in three of the 33 unrelated patients (9%), and a fourth mutation was found in the two sisters. No BMPR2 mutations were identified in the 130 normal controls. This difference in frequency was statistically significant. Moreover, the mutation-positive patients had a somewhat shorter duration of fenfluramine exposure before illness than the mutation-negative patients, a difference that was statistically significant when the two sisters were included in the analysis. In conclusion, the present authors have detected bone morphogenetic protein receptor 2 mutations that appear to be rare in the general population but may combine with exposure to fenfluramine derivatives to greatly increase the risk of developing severe pulmonary arterial hypertension.