Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A2B receptor (A2BR)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A2BR has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.
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Supported by US National Institute of Health grants DK077748 (to Y.X.), DK083559 (to Y.X.), HL070952 (to M.R.B.) and HL092188 (to H.K.E.) and by China National Science Foundation Scholarship Council 2008637068 (to J.W.). We thank T. Krahn (Bayer HealthCare AG) for the adenosine receptor A2BR agonist BAY 60-6583. Adenosine receptor–deficient mice were obtained from the following sources: A1R-deficient mice (J. Schnermann, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health); A2AR-deficient mice (J.-F. Chen, Boston University School of Medicine); A2BR-deficient mice (M.R. Blackburn, University of Texas–Houston Medical School); and A3R-deficient mice (M. Jacobson, Merck Research Laboratories).
The authors declare no competing financial interests.
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