Erythrocytes Retain Hypoxic Adenosine Response for Faster Acclimatization Upon Re-Ascent

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

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