title: Hyperoxia synergizes with mutant bone morphogenic protein receptor 2 to cause metabolic stress, oxidant injury, and pulmonary hypertension.
abstract: Pulmonary arterial hypertension (PAH) has been associated with a number of different but interrelated pathogenic mechanisms. Metabolic and oxidative stresses have been shown to play important pathogenic roles in a variety of model systems. However, many of these relationships remain at the level of association. We sought to establish a direct role for metabolic stress and oxidant injury in the pathogenesis of PAH. Mice that universally express a disease-causing mutation in bone morphogenic protein receptor 2 (Bmpr2) were exposed to room air or to brief daily hyperoxia (95% oxygen for 3 h) for 6 weeks, and were compared with wild-type animals undergoing identical exposures. In both murine tissues and cultured endothelial cells, the expression of mutant Bmpr2 was sufficient to cause oxidant injury that was particularly pronounced in mitochondrial membranes. With the enhancement of mitochondrial generation of reactive oxygen species by hyperoxia, oxidant injury was substantially enhanced in mitochondrial membranes, even in tissues distant from the lung. Hyperoxia, despite its vasodilatory actions in the pulmonary circulation, significantly worsened the PAH phenotype (elevated right ventricular systolic pressure, decreased cardiac output, and increased pulmonary vascular occlusion) in Bmpr2 mutant animals. These experiments demonstrate that oxidant injury and metabolic stress contribute directly to disease development, and provide further evidence for PAH as a systemic disease with life-limiting cardiopulmonary manifestations.
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Fessel
authors.forename: Charles R
authors.initials: CR
authors.lastname: Flynn
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Robinson
authors.forename: Niki L
authors.initials: NL
authors.lastname: Penner
authors.forename: Santhi
authors.initials: S
authors.lastname: Gladson
authors.forename: Christie J
authors.initials: CJ
authors.lastname: Kang
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
authors.forename: James D
authors.initials: JD
authors.lastname: West
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D002302:Cardiac Output; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D018496:Hyperoxia / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply*; D055370:Lung Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D018384:Oxidative Stress; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
chemical_list: D017382:Reactive Oxygen Species; C498218:BMPR2 protein, human; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II