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

TY - JOUR

T1 - On the antioxidant properties of erythropoietin and its association with the oxidative–nitrosative stress response to hypoxia in humans

AU - Bailey, D M

AU - Lundby, C

AU - Berg, R M G

AU - Taudorf, S

AU - Rahmouni, H

AU - Gutowski, M

AU - Mulholland, C W

AU - Sullivan, J L

AU - Swenson, E R

AU - McEneny, J

AU - Young, I S

AU - Pedersen, Bente Klarlund

AU - Møller, Kirsten

AU - Pietri, S

AU - Culcasi, M

N1 - © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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˙), 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 × 1011 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). 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. Copyright

AB - 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˙), 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 × 1011 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). 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. Copyright

KW - Adult

KW - Anoxia

KW - Antioxidants

KW - Electron Spin Resonance Spectroscopy

KW - Enzyme-Linked Immunosorbent Assay

KW - Erythropoietin

KW - Humans

KW - Luminescence

KW - Male

KW - Nitrosation

KW - Oxidative Stress

U2 - 10.1111/apha.12313

DO - 10.1111/apha.12313

M3 - Journal article

C2 - 24811856

SN - 1748-1708

VL - 212

SP - 175

EP - 187

JO - Acta Physiologica

JF - Acta Physiologica

IS - 2

ER -