TY - JOUR
T1 - Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent
AU - Song, Anren
AU - Zhang, Yujin
AU - Han, Leng
AU - Yegutkin, Gennady G.
AU - Liu, Hong
AU - Sun, Kaiqi
AU - D'Alessandro, Angelo
AU - Li, Jessica
AU - Karmouty-Quintana, Harry
AU - Iriyama, Takayuki
AU - Weng, Tingting
AU - Zhao, Shushan
AU - Wang, Wei
AU - Wu, Hongyu
AU - Nemkov, Travis
AU - Subudhi, Andrew W.
AU - Jameson-Van Houten, Sonja
AU - Julian, Colleen G.
AU - Lovering, Andrew T.
AU - Hansen, Kirk C.
AU - Zhang, Hong
AU - Bogdanov, Mikhail
AU - Dowhan, William
AU - Jin, Jianping
AU - Kellems, Rodney E.
AU - Eltzschig, Holger K.
AU - Blackburn, Michael
AU - Roach, Robert C.
AU - Xia, Yang
N1 - Publisher Copyright:
© The Author(s) 2017.
PY - 2017/2/7
Y1 - 2017/2/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85011914857&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85011914857&partnerID=8YFLogxK
U2 - 10.1038/ncomms14108
DO - 10.1038/ncomms14108
M3 - Article
C2 - 28169986
AN - SCOPUS:85011914857
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 14108
ER -