Open AccessDifferential IL‐1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling
Author(s) -
Pickworth Josephine,
Rothman Alexander,
Iremonger James,
Casbolt Helen,
Hopkinson Kay,
Hickey Peter M.,
Gladson Santhi,
Shay Sheila,
Morrell Nicholas W.,
Francis Sheila E.,
West James D.,
Lawrie Allan
Publication year - 2017
Publication title -
pulmonary circulation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.791
H-Index - 40
ISSN - 2045-8940
DOI - 10.1177/2045893217729096
Subject(s) - bmpr2 , medicine , bone morphogenetic protein , osteoprotegerin , pulmonary artery , pulmonary hypertension , lung , vascular remodelling in the embryo , signal transduction , endocrinology , receptor , microbiology and biotechnology , biology , gene , biochemistry , activator (genetics)
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.