Nature medicine, 2011-01, Vol.17 (1), p.79
2011
Details
- Autor(en) / Beteiligte
- Titel
- Detrimental effects of adenosine signaling in sickle cell disease
- Ist Teil von
- Nature medicine, 2011-01, Vol.17 (1), p.79
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2011
- Link zum Volltext
- Beschreibungen/Notizen
- 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 A(2B) receptor (A(2B)R)-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 A(2B)R has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.
- Sprache
- Englisch
- Identifikatoren
- eISSN: 1546-170XDOI: 10.1038/nm.2280Titel-ID: cdi_pubmed_primary_21170046
- Format
- –
- Schlagworte
- Adenosine - blood, Adenosine - physiology, Adenosine - therapeutic use, Adenosine - toxicity, Adenosine Deaminase - deficiency, Adenosine Deaminase - therapeutic use, Anemia, Sickle Cell - blood, Anemia, Sickle Cell - drug therapy, Anemia, Sickle Cell - physiopathology, Animals, Hemolysis, Humans, Kidney - drug effects, Kidney - pathology, Liver - drug effects, Liver - pathology, Lung - drug effects, Lung - pathology, Mice, Mice, Knockout, Mice, Transgenic, Receptor, Adenosine A2B - physiology, Signal Transduction - physiology, Spleen - drug effects, Spleen - pathology, Xanthines - therapeutic use