Abstract
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-1α, HIF-2α, NF-κB 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-1α mRNA levels over time reaching a peak after 24 h. Whereas, HIF-2α and NRF2 mRNA levels increased over time. In contrast, the NF-κB mRNA levels remained unchanged. Plasma levels of IL-1β and IL-6 also remained within normal ranges. ROS production rate and markers of OxS damage were significantly increased over time. The analysis of TF-gene expression suggests that HIF-1α is a lead TF during sub-acute HH exposure. The prolongation of the HH exposure led to a switch between HIF-1α and HIF-2α/NRF2, suggesting the activation of new pathways. These results provide new insights regarding the temporal regulation of TFs, inflammatory state, and ROS homeostasis involved in human hypoxic response, potentially also relevant to the mediation of diseases that induce a hypoxic state.
Highlights
Www.nature.com/scientificreports posttranslational hydroxylation of conserved proline and asparagine residues
All the subjects included in data analysis had a value of Lake Louise Score (LLS) < 3 during three days of exposure to high-altitude hypoxia
We have identified in vivo differential temporal regulation of molecular aspects of HIFs and other master transcription factors (TFs) in healthy humans in direct response to hypobaric hypoxia (HH)-induced inflammation and oxidative stress (OxS) (Fig. 4)
Summary
Www.nature.com/scientificreports posttranslational hydroxylation of conserved proline and asparagine residues. Since the 1990s10,11, previous research has shown that HIFs modulate the transcriptional response to hypoxia under both physiological and pathological conditions This includes the expression of approximately 1000 genes that are broadly involved in the coordination of hypoxic adaptation; including those regulating metabolism, blood-vessel growth, cell division, inflammation and OxS response[12,13]. This study gives a unique insight into regulatory processes governing the early phase of hypoxic response in relation to inflammation and OxS in humans in vivo, as well as providing new knowledge specific to the molecular regulation of HIFs, and other master TFs, in a cellular population implied in the pathogenesis of several cardiovascular diseases
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