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 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

Manual / Issue 10 / Polychrome

Manual, a journal about art and its making. Polychrome. In art, especially, polychrome invites us to the dialogue that colors are always having amongst themselves. A history of polychrome could be a series of poems exchanged among colors. The exchange might exhibit something like perpetual newness, again and again revealing differently bent hues and movingly novel blends. It would be a short-line poetry, excruciatingly sensitive to tone. Its speakers would have no names, so it would confuse the psychology of human orientation. In this connection, a warning against rendering polychrome as a pure positive seems in order: the parties to this dialogue talk at cross-purposes, always on the brink of divorcing. Polychrome can offend and destroy. It conscripts discrete colors in order to sacrifice them. Does polychrome offend by mocking our own failure to connect? In any case, polychrome has an advanced idiom for dealing with conflict. It’s at home with uncertainty. —Darby English, from the introduction to Issue 10: Polychrome. Softcover, 80 pages. Published 2018 by the RISD Museum. Manual 10 (Polychrome) contributors include David Batchelor, Gina Borromeo, Nicole Buchanan, Catherine Cooper, Darby English, Mara L. Hermano, Elon Cook Lee, Josephine Lee, Evelyn Lincoln, Dominic Molon, Maureen C. O\u27Brien, RISD Museum 2017 Summer Teen Intensive Students, and Elizabeth A. Williams.https://digitalcommons.risd.edu/risdmuseum_journals/1036/thumbnail.jp

A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

Abstract: Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH

Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH

Links between dysfunctional Bone Morphogenetic Protein signalling and Interleukin-1ß mediated inflammation in pulmonary arterial hypertension

Rationale: Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in up to 70% of patients with heritable and up to 25% with idiopathic pulmonary arterial hypertension, however penetrance within families with the same mutation is low implying the necessity for a ‘second hit’. Inflammatory cytokines are raised in patients with PAH, and in animal models have been shown to play a modulating role in disease pathogenesis. Objective: To determine whether there is a pulmonary specific interplay between BMPR2 deficiency and inflammatory Interleukin 1ß (IL-1ß) signalling that may explain the local manifestation of PAH in the lung. Methods and Results: mRNA microarray analysis of RNA isolated from pulmonary artery (PASMC) and aortic (AoSMC) smooth muscle cells demonstrated reduced inflammatory pathway activation in response to IL-1ß in PASMC compared with AoSMCs. However, further microarray analysis of PASMCs analysis demonstrated an exaggerated inflammatory response to IL-1ß upon loss of BMPR2 signalling. To determine whether IL-1ß supplementation would exacerbate disease phenotype on the background of a BMPR2 mutation, R899X+/- BMPR2 transgenic mice fed western diet for six weeks were given daily injections of IL-1ß. IL-1ß treated mice had higher white blood cell counts, demonstrating effective administration of IL-1ß. Raised serum protein levels of Interleukin-6 and Osteoprotegerin recapitulating in vitro PASMC data. Phenotypically, IL-1ß treated mice demonstrated a significant increase in pulmonary vascular remodelling. Conclusion: IL-1ß induces a pulmonary artery-specific transcriptome that is altered by suppression of BMPR2 signalling in vitro. In vivo and in vitro IL-1ß drives an exaggerated inflammatory response under conditions where BMPR2 signalling is reduced

A diagnostic miRNA signature for pulmonary arterial hypertension using a consensus machine learning approach.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare but life shortening disease, the diagnosis of which is often delayed, and requires an invasive right heart catheterisation. Identifying diagnostic biomarkers may improve screening to identify patients at risk of PAH earlier and provide new insights into disease pathogenesis. MicroRNAs are small, non-coding molecules of RNA, previously shown to be dysregulated in PAH, and contribute to the disease process in animal models. METHODS: Plasma from 64 treatment naïve patients with PAH and 43 disease and healthy controls were profiled for microRNA expression by Agilent Microarray. Following quality control and normalisation, the cohort was split into training and validation sets. Four separate machine learning feature selection methods were applied to the training set, along with a univariate analysis. FINDINGS: 20 microRNAs were identified as putative biomarkers by consensus feature selection from all four methods. Two microRNAs (miR-636 and miR-187-5p) were selected by all methods and used to predict PAH diagnosis with high accuracy. Integrating microRNA expression profiles with their associated target mRNA revealed 61 differentially expressed genes verified in two independent, publicly available PAH lung tissue data sets. Two of seven potentially novel gene targets were validated as differentially expressed in vitro in human pulmonary artery smooth muscle cells. INTERPRETATION: This consensus of multiple machine learning approaches identified two miRNAs that were able to distinguish PAH from both disease and healthy controls. These circulating miRNA, and their target genes may provide insight into PAH pathogenesis and reveal novel regulators of disease and putative drug targets. FUNDING: This work was supported by a National Institute for Health Research Rare Disease Translational Research Collaboration (R29065/CN500) and British Heart Foundation Project Grant (PG/11/116/29288)