On the antioxidant properties of erythropoietin and its association with the oxidative-nitrosative stress response to hypoxia in humans

    Authors

    D. M. Bailey; C. Lundby; R. M. G. Berg; S. Taudorf; H. Rahmouni; M. Gutowski; C. W. Mulholland; J. L. Sullivan; E. R. Swenson; J. McEneny; I. S. Young; B. K. Pedersen; K. Moller; S. Pietri;M. Culcasi

    Comments

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    Abbreviated Journal Title

    Acta Physiol.

    Keywords

    antioxidants; erythropoietin; free radicals; hypoxia; iron chelation; ACUTE MOUNTAIN-SICKNESS; DYNAMIC CEREBRAL AUTOREGULATION; HYDROXYL; RADICALS; ALPHA-TOCOPHEROL; BARRIER FUNCTION; VITAMIN-C; ASCORBATE; PLASMA; CAPACITY; DAMAGE; Physiology

    Abstract

    Aim: 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 center dot), 2,2-diphenyl-1-picrylhydrazyl (DPPH center dot) and peroxyl (ROO center dot) 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(center dot-)) and N-tert-butyl-a-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 center dot (k(r) = 1.03-1.66 x 10(11) M-1 s(-1)) with the capacity to inhibit Fenton chemistry through catalytic iron chelation. Its ability to scavenge DPPH. and ROO center dot 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(center dot-), 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). Conclusion: 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.

    Journal Title

    Acta Physiologica

    Volume

    212

    Issue/Number

    2

    Publication Date

    1-1-2014

    Document Type

    Article

    Language

    English

    First Page

    175

    Last Page

    187

    WOS Identifier

    WOS:000341828700009

    ISSN

    1748-1708

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