title: Detrimental effects of adenosine signaling in sickle cell disease.
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 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Dai
authors.forename: Jiaming
authors.initials: J
authors.lastname: Wen
authors.forename: Weiru
authors.initials: W
authors.lastname: Zhang
authors.forename: Almut
authors.initials: A
authors.lastname: Grenz
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
authors.forename: Guangxiu
authors.initials: G
authors.lastname: Lu
authors.forename: Danny C
authors.initials: DC
authors.lastname: Alexander
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.forename: Louvenia
authors.initials: L
authors.lastname: Carter-Dawson
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Lewis
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Harinder S
authors.initials: HS
authors.lastname: Juneja
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000241:Adenosine / Q000097:blood / Q000502:physiology* / Q000627:therapeutic use / Q000633:toxicity; D000243:Adenosine Deaminase / Q000172:deficiency / Q000627:therapeutic use; D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D006461:Hemolysis; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D043704:Receptor, Adenosine A2B / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D014970:Xanthines / Q000627:therapeutic use
chemical_list: C518874:1-propyl-8-(4-sulfophenyl)xanthine; D043704:Receptor, Adenosine A2B; D014970:Xanthines; D000243:Adenosine Deaminase; C051409:pegademase bovine; D000241:Adenosine