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Circulation. 2019 Oct 22;140(17):1409-1425. doi: 10.1161/CIRCULATIONAHA.119.040629. Epub 2019 Aug 29.

Phenotypically Silent Bone Morphogenetic Protein Receptor 2 Mutations Predispose Rats to Inflammation-Induced Pulmonary Arterial Hypertension by Enhancing the Risk for Neointimal Transformation.

Author information

1
Veterans Affairs Palo Alto Health Care System, CA (W.T, X.J., Y.K.S., E.S., A.B.T., G.P., Y.K., P.Z., S.P., P.D., M.R.N.).
2
Stanford University School of Medicine, CA (W.T., X.J., Y.K.S., E.S., T.H.W., P.N.K., A.B.T., A.C., L.W., G.P., Y.K., P.Z., J.C., S.P., P.D., P.M., H.C., R.Z., M.P.S., M.R., M.R.N.).
3
Faculté de Médecine, Université Paris-Sud and Université Paris-Saclay, Le Kremlin-Bicêtre, France (P.D., M.H.).
4
Institut National de la Sante Et de la Recherche Medicale UMR_S 999, Le Plessis-Robinson, France (P.D., M.H.).
5
Pathology Department, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France (P.D.).
6
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, China (G.P.).
7
University of Michigan Health System, Ann Arbor (M.P.G.).
8
Free University Medical Center Amsterdam, the Netherlands (N.F.V.).
9
AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, Department Hospitalo-Universitaire Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (M.H.).

Abstract

BACKGROUND:

Bmpr2 (bone morphogenetic protein receptor 2) mutations are critical risk factors for hereditary pulmonary arterial hypertension (PAH) 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-LO (5-lipoxygenase) provokes lung inflammation and transient PAH in Bmpr2+/- mice. Accordingly, 5-LO and its metabolite, leukotriene B4, 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.

METHODS:

Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to 1 year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO-expressing adenovirus, monocrotaline, SU5416, SU5416 with chronic hypoxia, or chronic hypoxia alone. Bmpr2-mutant hereditary PAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells with impaired BMPR2 signaling were exposed to increased 5-LO-mediated inflammation and were assessed for phenotypic and transcriptomic changes.

RESULTS:

Lung inflammation, induced by intratracheal delivery of 5-LO-expressing adenovirus, elicited severe PAH with intimal remodeling in Bmpr2+/- rats but not in their wild-type littermates. Neointimal lesions in the diseased Bmpr2+/- rats gained endogenous 5-LO expression associated with elevated leukotriene B4 biosynthesis. Bmpr2-mutant hereditary PAH patients similarly expressed 5-LO in the neointimal cells. In vitro, BMPR2 deficiency, compounded by 5-LO-mediated inflammation, generated apoptosis-resistant and proliferative pulmonary artery endothelial cells with mesenchymal characteristics. These transformed cells expressed nuclear envelope-localized 5-LO consistent with induced leukotriene B4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated nuclear factor Kappa B subunit (NF-κB), interleukin-6, and transforming growth factor beta (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.

CONCLUSIONS:

In a new 2-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 leukotriene B4 production. This study offers an explanation of how an environmental injury unleashes the destructive potential of an otherwise silent genetic mutation.

KEYWORDS:

bmpr2 receptor; endothelial cells; inflammation; lung

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