Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling
Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in patients with heritable and idiopathic pulmonary arterial hypertension (PAH). Circulating levels of interleukin-1 (IL-1) are raised in patients and animal models. Whether interplay between BMP and IL-1 signaling can explain...
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2017-09-01
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Series: | Pulmonary Circulation |
Online Access: | https://doi.org/10.1177/2045893217729096 |
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doaj-269ad62df14a47e7a87b0dca7a1a883a2020-11-25T03:20:48ZengSAGE PublishingPulmonary Circulation2045-89402017-09-01710.1177/2045893217729096Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodelingJosephine Pickworth0Alexander Rothman1James Iremonger2Helen Casbolt3Kay Hopkinson4Peter M. Hickey5Santhi Gladson6Sheila Shay7Nicholas W. Morrell8Sheila E. Francis9James D. West10Allan Lawrie11Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UKDepartment of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UKDepartment of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UKDepartment of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UKDepartment of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UKDepartment of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UKVanderbilt Institute, Nashville, TN, USAVanderbilt Institute, Nashville, TN, USADepartment of Medicine, University of Cambridge, Cambridge, UKDepartment of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UKVanderbilt Institute, Nashville, TN, USADepartment of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, UKBone morphogenetic protein receptor type 2 (BMPR2) mutations are present in patients with heritable and idiopathic pulmonary arterial hypertension (PAH). Circulating levels of interleukin-1 (IL-1) are raised in patients and animal models. Whether interplay between BMP and IL-1 signaling can explain the local manifestation of PAH in the lung remains unclear. Cell culture, siRNA, and mRNA microarray analysis of RNA isolated from human pulmonary artery (PASMC) and aortic (AoSMC) smooth muscle cells were used. R899X +/– BMPR2 transgenic mice fed a Western diet for six weeks were given daily injections of IL-1ß prior to assessment for PAH and tissue collection. PASMC have reduced inflammatory activation in response to IL-1ß compared with AoSMCs; however, PASMC with reduced BMPR2 demonstrated an exaggerated response. Mice treated with IL-1ß had higher white blood cell counts and significantly raised serum protein levels of IL-6 and osteoprotegerin (OPG) plasma levels recapitulating in vitro data. Phenotypically, IL-1ß treated mice demonstrated increased pulmonary vascular remodeling. IL-1ß induces an exaggerated pulmonary artery specific transcriptomic inflammatory response when BMPR2 signaling is reduced.https://doi.org/10.1177/2045893217729096 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Josephine Pickworth Alexander Rothman James Iremonger Helen Casbolt Kay Hopkinson Peter M. Hickey Santhi Gladson Sheila Shay Nicholas W. Morrell Sheila E. Francis James D. West Allan Lawrie |
spellingShingle |
Josephine Pickworth Alexander Rothman James Iremonger Helen Casbolt Kay Hopkinson Peter M. Hickey Santhi Gladson Sheila Shay Nicholas W. Morrell Sheila E. Francis James D. West Allan Lawrie Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling Pulmonary Circulation |
author_facet |
Josephine Pickworth Alexander Rothman James Iremonger Helen Casbolt Kay Hopkinson Peter M. Hickey Santhi Gladson Sheila Shay Nicholas W. Morrell Sheila E. Francis James D. West Allan Lawrie |
author_sort |
Josephine Pickworth |
title |
Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling |
title_short |
Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling |
title_full |
Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling |
title_fullStr |
Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling |
title_full_unstemmed |
Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling |
title_sort |
differential il-1 signaling induced by bmpr2 deficiency drives pulmonary vascular remodeling |
publisher |
SAGE Publishing |
series |
Pulmonary Circulation |
issn |
2045-8940 |
publishDate |
2017-09-01 |
description |
Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in patients with heritable and idiopathic pulmonary arterial hypertension (PAH). Circulating levels of interleukin-1 (IL-1) are raised in patients and animal models. Whether interplay between BMP and IL-1 signaling can explain the local manifestation of PAH in the lung remains unclear. Cell culture, siRNA, and mRNA microarray analysis of RNA isolated from human pulmonary artery (PASMC) and aortic (AoSMC) smooth muscle cells were used. R899X +/– BMPR2 transgenic mice fed a Western diet for six weeks were given daily injections of IL-1ß prior to assessment for PAH and tissue collection. PASMC have reduced inflammatory activation in response to IL-1ß compared with AoSMCs; however, PASMC with reduced BMPR2 demonstrated an exaggerated response. Mice treated with IL-1ß had higher white blood cell counts and significantly raised serum protein levels of IL-6 and osteoprotegerin (OPG) plasma levels recapitulating in vitro data. Phenotypically, IL-1ß treated mice demonstrated increased pulmonary vascular remodeling. IL-1ß induces an exaggerated pulmonary artery specific transcriptomic inflammatory response when BMPR2 signaling is reduced. |
url |
https://doi.org/10.1177/2045893217729096 |
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