Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 46, Issue 2, Pages 321-326Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2008.10.047
Keywords
Hypoxia; DNA oxidation; Protein oxidation; HIF-1 alpha expression; EPO; VEGF
Funding
- Alberta Heritage Foundation for Medical Research (AHFMR)
- Heart and Stroke Foundation of Alberta, NWT, and Nunavut
- Canadian Foundation for innovation
- AHFMR
- Natural Research and Engineering Research Council of Canada (NSERC)
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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 (PETO2=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 ill 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. (C) 2008 Elsevier Inc. All rights reserved.
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