Abstract
Ascent to high altitude feels uncomfortable in part because of a decreased partial pressure of oxygen due to the decrease in barometric pressure. The molecular mechanisms causing injury in liver tissue after exposure to a hypoxic environment are widely unknown. The liver must physiologically and metabolically change to improve tolerance to altitude-induced hypoxia. Since the liver is the largest metabolic organ and regulates many physiological and metabolic processes, it plays an important part in high altitude adaptation. The cellular response to hypoxia results in changes in the gene expression profile. The present study explores these changes in a rat model. To comprehensively investigate the gene expression and physiological changes under hypobaric hypoxia, we used genome-wide transcription profiling. Little is known about the genome-wide transcriptional response to acute and chronic hypobaric hypoxia in the livers of rats. In this study, we carried out RNA-Sequencing (RNA-Seq) of liver tissue from rats in three groups, normal control rats (L), rats exposed to acute hypobaric hypoxia for 2 weeks (W2L) and rats chronically exposed to hypobaric hypoxia for 4 weeks (W4L), to explore the transcriptional profile of acute and chronic mountain sickness in a mammal under a controlled time-course. We identified 497 differentially expressed genes between the three groups. A principal component analysis revealed large differences between the acute and chronic hypobaric hypoxia groups compared with the control group. Several immune-related and metabolic pathways, such as cytokine-cytokine receptor interaction and galactose metabolism, were highly enriched in the KEGG pathway analysis. Similar results were found in the Gene Ontology analysis. Cogena analysis showed that the immune-related pathways were mainly upregulated and enriched in the acute hypobaric hypoxia group.
Highlights
The defining feature of a high altitude environment is sustained hypobaric hypoxic conditions
Exposure to high altitudes may result in acute mountain sickness (AMS), a syndrome causing headaches and other symptoms occurring at altitudes >2,500 m (Honigman et al, 1993; Roach et al, 2018)
Adult Sprague-Dawley male rats were randomly allocated to 3 groups (4 animals per group) containing normal rats (L), rats exposed to hypobaric hypoxia for 2 weeks (W2L) and rats exposed to chronic hypobaric hypoxia for 4 weeks (W4L), as suggest in the article of Ni et al (2014)
Summary
The defining feature of a high altitude environment is sustained hypobaric hypoxic conditions. Many other studies have reported a downregulation of the expression and/or activity of FAO enzymes, many of which are PPARα targets, both in human muscle at altitude and in the heart and skeletal muscle of hypoxic rodents (Horscroft et al, 2017). This might indicate a failure to fully compensate for the lower oxygen availability or may itself form part of the acclimatization process, but it involves changes in gene expression and appears to be a regulated response. Exposure to hypoxia promotes the expression of transcription factors, including nuclear factor NFκB (NF-κB), which plays a central role
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