A1 Refereed original research article in a scientific journal
Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent
Authors: Song AR, Zhang YJ, Han L, Yegutkin GG, Liu H, Sun KQ, D'Alessandro A, Li J, Karmouty-Quintana H, Iriyama T, Weng TT, Zhao SS, Wang W, Wu HY, Nemkov T, Subudhi AW, Jameson-Van Houten S, Julian CG, Lovering AT, Hansen KC, Zhang H, Bogdanov M, Dowhan W, Jin JP, Kellems RE, Eltzschig HK, Blackburn M, Roach RC, Xia Y, Xia Y
Publisher: NATURE PUBLISHING GROUP
Publication year: 2017
Journal: Nature Communications
Journal name in source: NATURE COMMUNICATIONS
Journal acronym: NAT COMMUN
Article number: ARTN 14108
Volume: 8
Number of pages: 13
ISSN: 2041-1723
DOI: https://doi.org/10.1038/ncomms14108
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/20548026
Faster acclimatization to high altitude upon re-ascent is seen in humans; however, the molecular basis for this enhanced adaptive response is unknown. We report that in healthy lowlanders, plasma adenosine levels are rapidly induced by initial ascent to high altitude and achieved even higher levels upon re-ascent, a feature that is positively associated with quicker acclimatization. Erythrocyte equilibrative nucleoside transporter 1 (eENT1) levels are reduced in humans at high altitude and in mice under hypoxia. eENT1 deletion allows rapid accumulation of plasma adenosine to counteract hypoxic tissue damage in mice. Adenosine signalling via erythrocyte ADORA2B induces PKA phosphorylation, ubiquitination and proteasomal degradation of eENT1. Reduced eENT1 resulting from initial hypoxia is maintained upon re-ascent in humans or re-exposure to hypoxia in mice and accounts for erythrocyte hypoxic memory and faster acclimatization. Our findings suggest that targeting identified purinergic-signalling network would enhance the hypoxia adenosine response to counteract hypoxia-induced maladaptation.
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