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

Anren Song; Yujin Zhang; Leng Han; Gennady G Yegutkin; Hong Liu; Kaiqi Sun; Angelo D'Alessandro; Jessica Li; Harry Karmouty-Quintana; Takayuki Iriyama; Tingting Weng; Shushan Zhao; Wei Wang; Hongyu Wu; Travis Nemkov; Andrew W Subudhi; Sonja Jameson-Van Houten; Colleen G Julian; Andrew T Lovering; Kirk C Hansen; Hong Zhang; Mikhail Bogdanov; William Dowhan; Jianping Jin; Rodney E Kellems; Holger K Eltzschig; Michael Blackburn; Robert C Roach; Yang Xia

doi:10.1038/ncomms14108

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

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

Authors

Anren Song¹, Yujin Zhang¹, Leng Han¹, Gennady G Yegutkin², Hong Liu^{1

3}, Kaiqi Sun^{1

3}, Angelo D'Alessandro⁴, Jessica Li¹, Harry Karmouty-Quintana¹, Takayuki Iriyama^{1

5}, Tingting Weng¹, Shushan Zhao^{1

6}, Wei Wang^{1

7}, Hongyu Wu¹, Travis Nemkov⁸, Andrew W Subudhi⁸, Sonja Jameson-Van Houten⁸, Colleen G Julian⁸, Andrew T Lovering⁸, Kirk C Hansen⁴, Hong Zhang⁹, Mikhail Bogdanov¹, William Dowhan¹, Jianping Jin¹, Rodney E Kellems^{1

3}, Holger K Eltzschig¹⁰, Michael Blackburn^{1

3}, Robert C Roach⁸, Yang Xia^{1

3

7}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

5'-Nucleotidase / blood
5'-Nucleotidase / metabolism
Acclimatization / physiology*
Adenosine / blood
Adenosine / metabolism*
Adult
Altitude
Altitude Sickness / blood
Altitude Sickness / physiopathology
Animals
Cyclic AMP-Dependent Protein Kinases / metabolism
Equilibrative Nucleoside Transporter 1 / blood
Equilibrative Nucleoside Transporter 1 / genetics
Equilibrative Nucleoside Transporter 1 / metabolism*
Erythrocytes / physiology*
Female
GPI-Linked Proteins / blood
GPI-Linked Proteins / metabolism
Healthy Volunteers
Humans
Hypoxia / blood
Hypoxia / physiopathology*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxygen / metabolism
Phosphorylation
Receptor, Adenosine A2B / genetics
Receptor, Adenosine A2B / metabolism*
Signal Transduction / physiology
Ubiquitination
Young Adult

Substances

ADORA2B protein, human
Equilibrative Nucleoside Transporter 1
GPI-Linked Proteins
Receptor, Adenosine A2B
SLC29A1 protein, human
SLC29A1 protein, mouse
Cyclic AMP-Dependent Protein Kinases
5'-Nucleotidase
NT5E protein, human
Adenosine
Oxygen

Abstract

Publication types

MeSH terms

Substances

Grants and funding