title: Antioxidants for the treatment of patients with severe angioproliferative pulmonary hypertension?
abstract: CONCLUSIONS
  Pathobiological mechanisms that contribute to pulmonary vasoconstriction, lung vascular remodeling, and the development of right heart failure include the generation of reactive oxygen and nitrogen species and the response of lung vascular and cardiac cells to these molecules. We review the information regarding oxidant stress balanced by antioxidant mechanisms and the role of oxidants and antioxidants in hypoxic pulmonary hypertension and their potential role in an animal model of severe pulmonary arterial hypertension (PAH).
  
  
  BACKGROUND
  In human lung tissue from patients with idiopathic PAH, we find reduced superoxide dismutase activity and high expression of the oxidant stress markers nitrotyrosine and 8-OH-guanosine. In the Sugen 5416/chronic hypoxia model of PAH, lung tissue expression of nitrotyrosine and hemeoxygenase 1 (HO-1) is substantial, while HO-1 expression in the failing right ventricle is decreased. This model, based on administration of the VEGF receptor blocker Sugen 5416 and chronic hypoxia (Su/Hx), reproduces many of the characteristic features of severe angioobliterative human PAH. Treatment of Su/Hx rats with protandim, which nuclear factor erythroid-2 related factor (Nrf2)-dependently upregulates the expression of genes encoding antioxidant enzymes, protects against right heart failure without affecting angioobliterative PAH.
  
  
  RESULTS
  In human severe PAH, patient survival is determined by the function of the stressed right ventricle; investigation of oxidative and nitrosative stresses and their potential contribution to right heart failure is necessary.
  
  
  CONCLUSIONS
  Antioxidant therapeutic strategies may be of benefit in the setting of human severe PAH. Whether antioxidant strategies affect lung vascular remodeling and/or prevent right heart failure remains to be examined.
authors.affiliation: Victoria Johnson Center for Lung Research, Virginia Commonwealth University, Richmond, VA 23298, USA. nvoelkel@mcvh-vcu.edu
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: Harm J
authors.initials: HJ
authors.lastname: Bogaard
authors.forename: Aysar
authors.initials: A
authors.lastname: Al Husseini
authors.forename: Laszlo
authors.initials: L
authors.lastname: Farkas
authors.forename: Jose
authors.initials: J
authors.lastname: Gomez-Arroyo
authors.forename: Ramesh
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000209:etiology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D000860:Hypoxia; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D018384:Oxidative Stress; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase