Detrimental effects of adenosine signaling in sickle cell disease

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
Nature medicine (Impact Factor: 27.36). 01/2011; 17(1):79-86. DOI: 10.1038/nm.2280
Source: PubMed


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.

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    • "The newly synthesized StAR is functional and plays a critical role in the transfer of cholesterol from the outer to the inner mitochondrial membrane, whereas mitochondrial import and processing to 30 kDa StAR protein terminate this action [140] [141] [142]. HbS polymerization is mediated by upstream activation of adenosine receptor A 2B R by hypoxia, and hemolysis of irreversibly sickled red blood cells increases adenosine bioavailability through conversion of ATP by ectonucleotidases CD39 and CD73, thus predisposing patients with SCD to sustained high levels of cAMP [143] [144]. From this point of view, steroidogenesis could be expected to be increased in these patients. "
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    • "Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. (Zhang et al. 2011). "
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    • "The pathogenic potential of Adora2b in chronic inflammation is not restricted to the lung. For example, Adora2b signaling was recently revealed to be detrimental in sickle cell anemia, a context in which elevated levels of extracellular adenosine-Adora2b signaling promotes red blood cell sickling, contributing to the pathogenesis of this disease [44]. "
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