Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent.
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.
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Anren
A
Song
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Yujin
Y
Zhang
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Leng
L
Han
Medicity Research Laboratory, University of Turku, 20520 Turku, Finland.
Gennady G
0000-0001-6684-7982
GG
Yegutkin
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Hong
H
Liu
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Kaiqi
K
Sun
Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, Colorado 80045, USA.
Angelo
A
D'Alessandro
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Jessica
J
Li
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Harry
H
Karmouty-Quintana
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Takayuki
T
Iriyama
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Tingting
T
Weng
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, China.
Shushan
S
Zhao
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, China.
Wei
W
Wang
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Hongyu
H
Wu
Altitude Research Center, Department of Emergency Medicine University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Travis
T
Nemkov
Altitude Research Center, Department of Emergency Medicine University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Andrew W
AW
Subudhi
Altitude Research Center, Department of Emergency Medicine University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Sonja
S
Jameson-Van Houten
Altitude Research Center, Department of Emergency Medicine University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Colleen G
CG
Julian
Altitude Research Center, Department of Emergency Medicine University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Andrew T
AT
Lovering
Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, Colorado 80045, USA.
Kirk C
KC
Hansen
Department of Pathology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Hong
H
Zhang
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Mikhail
M
Bogdanov
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
William
W
Dowhan
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Jianping
J
Jin
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Rodney E
RE
Kellems
Organ Protection Program, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Holger K
HK
Eltzschig
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Michael
M
Blackburn
Altitude Research Center, Department of Emergency Medicine University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Robert C
RC
Roach
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, China.
Yang
Y
Xia
D015720:5'-Nucleotidase / Q000097:blood / Q000378:metabolism; D000064:Acclimatization / Q000502:physiology*; D000241:Adenosine / Q000097:blood / Q000378:metabolism*; D000328:Adult; D000531:Altitude; D000532:Altitude Sickness / Q000097:blood / Q000503:physiopathology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D033721:Equilibrative Nucleoside Transporter 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000502:physiology*; D005260:Female; D058851:GPI-Linked Proteins / Q000097:blood / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D054875:Ubiquitination; D055815:Young Adult
C000628986:ADORA2B protein, human; D033721:Equilibrative Nucleoside Transporter 1; D058851:GPI-Linked Proteins; D043704:Receptor, Adenosine A2B; C438649:SLC29A1 protein, human; C498476:SLC29A1 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D000241:Adenosine; D010100:Oxygen