Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia

Journal of Applied Physiology - Tập 116 Số 7 - Trang 893-904 - 2014
Nayia Petousi1, Quentin P. P. Croft2, Gianpiero L. Cavalleri3, Hung‐Yuan Cheng2, Federico Formenti4, Kōji Ishida5, Daniel Lunn6, Mark McCormack3, Kevin V. Shianna7, Nick P. Talbot2, Peter J. Ratcliffe4, Peter A. Robbins2
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
21Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
32Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland;
43Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom;
54Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan;
65Department of Statistics, University of Oxford, Oxford, United Kingdom; and
76Duke University, Durham, North Carolina;

Tóm tắt

Tibetan natives have lived on the Tibetan plateau (altitude ∼4,000 m) for at least 25,000 years, and as such they are adapted to life and reproduction in a hypoxic environment. Recent studies have identified two genetic loci, EGLN1 and EPAS1, that have undergone natural selection in Tibetans, and further demonstrated an association of EGLN1/ EPAS1 genotype with hemoglobin concentration. Both genes encode major components of the hypoxia-inducible factor (HIF) transcriptional pathway, which coordinates an organism's response to hypoxia. Patients living at sea level with genetic disease of the HIF pathway have characteristic phenotypes at both the integrative-physiology and cellular level. We sought to test the hypothesis that natural selection to hypoxia within Tibetans results in related phenotypic differences. We compared Tibetans living at sea level with Han Chinese, who are Tibetans' most closely related major ethnic group. We found that Tibetans had a lower hemoglobin concentration, a higher pulmonary ventilation relative to metabolism, and blunted pulmonary vascular responses to both acute (minutes) and sustained (8 h) hypoxia. At the cellular level, the relative expression and hypoxic induction of HIF-regulated genes were significantly lower in peripheral blood lymphocytes from Tibetans compared with Han Chinese. Within the Tibetans, we found a significant correlation between both EPAS1 and EGLN1 genotype and the induction of erythropoietin by hypoxia. In conclusion, this study provides further evidence that Tibetans respond less vigorously to hypoxic challenge. This is evident at sea level and, at least in part, appears to arise from a hyporesponsive HIF transcriptional system.

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Journal of Applied Physiology

Tập 116 Số 7

893-904

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