title: Hypoxia inhibits expression and function of mitochondrial thioredoxin 2 to promote pulmonary hypertension.
abstract: Pulmonary hypertension (PH) is characterized by increased pulmonary vascular resistance, pulmonary vascular remodeling, and increased pulmonary vascular pressures that often result in right ventricular dysfunction, leading to right heart failure. Evidence suggests that reactive oxygen species (ROS) contribute to PH pathogenesis by altering pulmonary vascular cell proliferation and intracellular signaling pathways. However, the role of mitochondrial antioxidants and oxidant-derived stress signaling in the development of hypoxia-induced PH is largely unknown. Therefore, we examined the role of the major mitochondrial redox regulator thioredoxin 2 (Trx2). Levels of Trx2 mRNA and protein were examined in human pulmonary arterial endothelial cells (HPAECs) and smooth muscle cells (HPASMCs) exposed to hypoxia, a common stimulus for PH, for 72 h. Hypoxia decreased Trx2 mRNA and protein levels. In vitro overexpression of Trx2 reduced hypoxia-induced H2O2production. The effects of increased Trx2 protein level were examined in transgenic mice expressing human Trx2 (TghTrx2) that were exposed to hypoxia (10% O2) for 3 wk. TghTrx2mice exposed to hypoxia had exacerbated increases in right ventricular systolic pressures, right ventricular hypertrophy, and increased ROS in the lung tissue. Trx2 overexpression did not attenuate hypoxia-induced increases in Trx2 oxidation or Nox4 expression. Expression of a dominant negative C93S Trx2 mutant that mimics Trx2 oxidation exacerbated hypoxia-induced increases in HPASMC H2O2levels and cell proliferation. In conclusion, Trx2 overexpression failed to attenuate hypoxia-induced HPASMC proliferation in vitro or hypoxia-induced PH in vivo. These findings indicate that strategies to enhance Trx2 expression are unlikely to exert therapeutic effects in PH pathogenesis.
authors.affiliation: Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and.
authors.forename: Sherry E
authors.initials: SE
authors.lastname: Adesina
authors.affiliation: Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and.
authors.forename: Brandy E
authors.initials: BE
authors.lastname: Wade
authors.affiliation: Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and.
authors.forename: Kaiser M
authors.initials: KM
authors.lastname: Bijli
authors.affiliation: Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and.
authors.forename: Bum-Yong
authors.initials: BY
authors.lastname: Kang
authors.affiliation: Department of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Clintoria R
authors.initials: CR
authors.lastname: Williams
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Young-Mi
authors.identifier: 0000-0003-3353-0844
authors.initials: YM
authors.lastname: Go
authors.affiliation: Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and.|Department of Medicine, Emory University, Atlanta, Georgia.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Hart
authors.affiliation: Department of Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia; and rsutlif@emory.edu.|Department of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Sutliff
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D050505:Mutant Proteins; D017382:Reactive Oxygen Species; D013879:Thioredoxins; D010100:Oxygen
keywords: human pulmonary artery smooth muscle cell; hydrogen peroxide; pulmonary hypertension; reactive oxygen species