title: On the antioxidant properties of erythropoietin and its association with the oxidative-nitrosative stress response to hypoxia in humans.
abstract: OBJECTIVE
  The aim of this study was to examine if erythropoietin (EPO) has the potential to act as a biological antioxidant and determine the underlying mechanisms.
  
  
  METHODS
  The rate at which its recombinant form (rHuEPO) reacts with hydroxyl (HO˙), 2,2-diphenyl-1-picrylhydrazyl (DPPH˙) and peroxyl (ROO˙) radicals was evaluated in-vitro. The relationship between the erythopoietic and oxidative-nitrosative stress response to poikilocapneic hypoxia was determined separately in-vivo by sampling arterial blood from eleven males in normoxia and following 12 h exposure to 13% oxygen. Electron paramagnetic resonance spectroscopy, ELISA and ozone-based chemiluminescence were employed for direct detection of ascorbate (A(˙-) ) and N-tert-butyl-α-phenylnitrone spin-trapped alkoxyl (PBN-OR) radicals, 3-nitrotyrosine (3-NT) and nitrite (NO2-).
  
  
  RESULTS
  We found rHuEPO to be a potent scavenger of HO˙ (kr = 1.03-1.66 × 10(11) m(-1) s(-1) ) with the capacity to inhibit Fenton chemistry through catalytic iron chelation. Its ability to scavenge DPPH˙ and ROO˙ was also superior compared to other more conventional antioxidants. Hypoxia was associated with a rise in arterial EPO and free radical-mediated reduction in nitric oxide, indicative of oxidative-nitrosative stress. The latter was confirmed by an increased systemic formation of A˙(-) , PBN-OR, 3-NT and corresponding loss of NO2- (P < 0.05 vs. normoxia). The erythropoietic and oxidative-nitrosative stress responses were consistently related (r = -0.52 to 0.68, P < 0.05).
  
  
  CONCLUSIONS
  These findings demonstrate that EPO has the capacity to act as a biological antioxidant and provide a mechanistic basis for its reported cytoprotective benefits within the clinical setting.
authors.affiliation: Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Treforest, UK; Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire UMR 7273, Équipe Sondes Moleculaires en Biologie et Stress Oxydant, Marseille, France.
authors.forename: D M
authors.initials: DM
authors.lastname: Bailey
authors.forename: C
authors.initials: C
authors.lastname: Lundby
authors.forename: R M G
authors.initials: RM
authors.lastname: Berg
authors.forename: S
authors.initials: S
authors.lastname: Taudorf
authors.forename: H
authors.initials: H
authors.lastname: Rahmouni
authors.forename: M
authors.initials: M
authors.lastname: Gutowski
authors.forename: C W
authors.initials: CW
authors.lastname: Mulholland
authors.forename: J L
authors.initials: JL
authors.lastname: Sullivan
authors.forename: E R
authors.initials: ER
authors.lastname: Swenson
authors.forename: J
authors.initials: J
authors.lastname: McEneny
authors.forename: I S
authors.initials: IS
authors.lastname: Young
authors.forename: B K
authors.initials: BK
authors.lastname: Pedersen
authors.forename: K
authors.initials: K
authors.lastname: Møller
authors.forename: S
authors.initials: S
authors.lastname: Pietri
authors.forename: M
authors.initials: M
authors.lastname: Culcasi
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D049449:Luminescence; D008297:Male; D015538:Nitrosation / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*
chemical_list: D000975:Antioxidants; D004921:Erythropoietin
keywords: antioxidants; erythropoietin; free radicals; hypoxia; iron chelation