Transcription Factors Regulation in Human Peripheral White Blood Cells during Hypobaric Hypoxia Exposure: an in-vivo experimental study

High altitude is a natural laboratory, within which the clinical study of human physiological response to hypobaric hypoxia (HH) is possible. Failure in the response results in progressive hypoxemia, inflammation and increased tissue oxidative stress (OxS). Thus, investigating temporal changes in key transcription factors (TFs) HIF-1 alpha, HIF-2 alpha, NF-kappa B and NRF2 mRNA levels, relative to OxS and inflammatory markers, may reveal molecular targets which contrast deleterious effects of hypoxia. Biological samples and clinical data from 15 healthy participants were collected at baseline and after rapid, passive ascent to 3830 m (24 h and 72 h). Gene expression was assessed by qPCR and ROS generation was determined by EPR spectroscopy. Oxidative damage and cytokine levels were estimated by immuno or enzymatic methods. Hypoxia transiently enhanced HIF-1 alpha mRNA levels over time reaching a peak after 24 h. Whereas, HIF-2 alpha and NRF2 mRNA levels increased overtime. In contrast, the NF-kappa B mRNA levels remained unchanged. Plasma levels of IL-1 beta and IL-6 also remained within normal ranges. ROS production rate and markers of OxS damage were significantly increased overtime. The analysis of TF-gene expression suggests that HIF-1 alpha is a lead TF during sub-acute HH exposure. The prolongation of the HH exposure led to a switch between HIF-1 alpha and HIF-2 alpha/NRF2, suggesting the activation of new pathways. These results provide new insights regarding the temporal regulation ofTFs, inflammatory state, and ROS homeostasis involved in human hypoxic response, potentially also relevant to the mediation of diseases that induce a hypoxic state.