Detrimental effects of adenosine signaling in sickle cell disease (Nat Med, 2011, 17:79-86)

報告日期: 2011/05/03
報告時間: 15:10/16:00
報告學生: 許佩玲
講評老師: 黃溫雅
附件下載:

Full Text: http://basicmed.med.ncku.edu.tw/admin/up_img/0503-1.pdf

Detrimental effects of adenosine signaling in sickle cell disease
Nature medicine 7, 79-86 (2011).
Yujin Zhang et al.
 
Speaker: Pei-Ling Hsu
Commentator: Dr. Wen-Ya Huang
Date: May-03-2011, 15:10-16:00
Location: Room 602
 
Abstract
Sickle-cell disease (SCD) is one of the most common severe monogenic disorders in the world. It is caused by a point mutation in the gene encoding β-globin, which results in sickle hemoglobin (HbS). Hypoxic conditions are known to promote deoxygenation and subsequent polymerization of HbS, resulting in red blood cell (RBC) sickling, hemolysis and eventual end organ damage. However, the specific factor and signaling pathways that are involved in sickle cell disease development still unclear. Using a high-throughput metabolomic screen, the authors find that adenosine and 2,3-diphosphoglycerate (2,3-DPG), an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, levels are elevated in the blood of SCD transgenic mice at steady state. Adenosine and 2,3-DPG concentrations are also significantly higher in the blood of humans with SCD than in the blood of control subjects. Elevated adenosine promotes RBC sickling, hemolysis and multi-tissue damage in SCD transgenic mice and promotes sickling of human erythrocytes. Moreover, activation of the A2B receptor (A2BR) by adenosine on erythrocytes increases 2,3-DPG levels through cAMP-dependent PKA activation, which reduces HbS oxygen affinity and promotes its polymerization and red blood cell sickling both in cultured human red blood cells and in SCD transgenic mice. Thus, these findings may provide evidences for the pathogenic consequences of excessive adenosine signaling in SCD. Interfering with adenosine signaling may be a new therapeutic strategy for this disease.
 
References
1.        Ingram, V.M. A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature 178, 792–794 (1956).
2.        Paszty, C. et al. Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease. Science 278, 876–878 (1997).
3.       Wallace, K.L. et al. NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-gamma and CXCR3 chemokines. Blood 114, 667–676 (2009).