Erythrocytes Retain "Hypoxic Purinergic Memory" for Faster Acclimatization upon Re-Ascent

Improved and faster acclimatization to high altitude upon re-ascent is seen in humans. However, molecular basis for initial acclimatization and retention upon re-ascent to high altitude remains largely unknown. Here we report that plasma adenosine levels are induced by high altitude and retained at higher levels upon re-ascent in health lowlanders and that its elevation is positively associated with quicker acclimatization upon re-ascent. Unexpectedly, we found that, 1) erythrocyte equilibrative nucleoside transporter 1 (eENT1) is the major adenosine transporter in erythrocyte. 2) eENT1 protein level is downregulated in both humans at high altitude and mice under hypoxia. 3) Deletion of eENT1 allows rapid accumulation of plasma adenosine to offset hypoxic tissue damage in mice. Mechanistically, 4) we revealed that ADORA2B-mediated PKA-dependent phosphorylation, ubiquitinization and proteasomal degradation underlies hypoxia-mediated reduced eENT1 protein. Thus, the reduced eENT1 resulting from the initial hypoxia establishes erythrocyte "hypoxic purinergic memory" to promote quicker and higher accumulation of plasma adenosine and faster acclimatization upon re-ascent.