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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, renderBmpr2 mutants susceptible to PAH. Overexpressing 5-LO (5-lipoxygenase) provokes lung inflammation and transient PAH inBmpr2 +/ -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 silentBmpr2 defects to elicit significant pulmonary vascular disease in rats.Methods: MonoallelicBmpr2 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 inBmpr2 +/- rats but not in their wild-type littermates. Neointimal lesions in the diseasedBmpr2 +/- 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 inBmpr2 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 inBmpr2 +/- 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.

circulation

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