Detrimental effects of adenosine signaling in sickle cell disease

Yujin Zhang, Yingbo Dai, Jiaming Wen, Weiru Zhang, Almut Grenz, Hong Sun, Lijian Tao, Guangxiu Lu, Danny C. Alexander, Michael V. Milburn, Louvenia Carter-Dawson, Dorothy E. Lewis, Wenzheng Zhang, Holger K. Eltzschig, Rodney E. Kellems, Michael R. Blackburn, Harinder S. Juneja, Yang Xia

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

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 (A2B 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 A2B R has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.

Original languageEnglish (US)
Pages (from-to)79-86
Number of pages8
JournalNature Medicine
Volume17
Issue number1
DOIs
StatePublished - Jan 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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