Relationships between oxidative stress, HIF‐1α transcription, erythropoietin and vascular endothelial growth factor during sustained hypoxia in humans

Abstract

The aim of this study was to investigate the relationships between reactive oxygen species (ROS), hypoxia inducible factor (HIF‐1α) transcription, and HIF‐1α target genes erythropoietin (EPO) and vascular endothelium growth factor (VEGF) in humans. Five healthy men (32±7 yrs, mean±SD) were exposed to 12 h of sustained hypoxia (PetO2=60 Torr). DNA oxidation (8‐Hydroxy‐2′‐deoxyguanosine, 8‐OHdG) oxidation protein products (AOPP), EPO and VEGF were measured in plasma and HIF‐1α mRNA was assessed in leucocytes before, and after 1, 2, 4, 6, 8, 10, 12 h of exposure to hypoxia.HIF‐1α mRNA amount increased during the first 2h of hypoxic exposure (+ 68%; p=0.03), then returned to baseline levels. VEGF increased at 4h (+121%; p=0.02) whereas EPO increased progressively from 4h to 12h (+114%; p<0.01). AOPP increased continuously from 4 h (+ 69%, p=0.04%) to 12h (+ 216 %, p=0.03) of hypoxic exposure while 8‐OHdG increased after 6 h (+ 78%, p<0.01) and remained elevated until 12h. During the “acute” increase phase of HIF‐1α (i.e., between 0 and 2h), 8‐OHdG was positively correlated with HIF‐1α (r=0.55, p=0.02).These findings demonstrate that hypoxia induces oxidative stress via an overproduction of ROS. Finally, this in vivo study in humans corroborates the previous in vitro findings demonstrating that ROS is involved in the stabilization of HIF‐1α transcription.Supported by Alberta Heritage Foundation for Medical Research, Heart & Stroke Foundation of Canada, Canadian Institutes of Health Research.