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Nat Commun. 2017 Feb 7;8:14108. doi: 10.1038/ncomms14108.

Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent.

Author information

1
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
2
Medicity Research Laboratory, University of Turku, 20520 Turku, Finland.
3
Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
4
Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, Colorado 80045, USA.
5
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
6
Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, China.
7
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, China.
8
Altitude Research Center, Department of Emergency Medicine University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
9
Department of Pathology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
10
Organ Protection Program, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.

Abstract

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.

PMID:
28169986
PMCID:
PMC5309698
DOI:
10.1038/ncomms14108
[Indexed for MEDLINE]
Free PMC Article

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