Relationship between oxidative stress and HIF-1α mRNA during sustained hypoxia in humans

The aim of this study was to investigate the relations among reactive oxygen species (ROS), hypoxia inducible factor (HIF-1 alpha) gene expression, HIF-1 alpha target gene erythropoietin (EPO), and vascular endothelium growth factor (VEGF) in humans. Five healthy men (32+/-7 years, mean+/-SD) were exposed to 12 h of sustained poikilocapnic hypoxia (P(ET)O(2)=60 mmHg). DNA oxidation (8-hydroxy-2'-deoxyguanosine, 8-OHdG), advanced oxidation protein products (AOPP), EPO, and VEGF were measured in plasma and HIF-1 alpha mRNA was assessed in leukocytes before and after 1, 2, 4, 6, 8, 10, and 12 h of exposure to hypoxia. HIF-1 alpha mRNA amount increased during the first two hours of hypoxic exposure and then returned to baseline levels. The findings reveal an up-regulation of HIF-1 alpha (+68%), VEGF (+46%), and EPO (+74%). AOPP increased continuously from 4 h (+69%) to 12 h (+216%) of hypoxic exposure while 8-OHdG increased after 6 h (+78%) and remained elevated until 12 h. During the "acute" increase phase of HIF-1 alpha (between 0 and 2 h), 8-OHdG was positively correlated with HIF-1 alpha (r=0.55). These findings suggest that hypoxia induces oxidative stress via an overgeneration of reactive oxygen species (ROS). Finally, this study in humans corroborates the previous in vitro findings demonstrating that ROS is involved in HIF-1 alpha transcription.