期刊
MEDICAL HYPOTHESES
卷 173, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.mehy.2023.111045
关键词
Purine nucleoside phosphorylase; Purine metabolism; Sickle cell disease; Hemolytic vasculopathy
Under hemolytic conditions, interaction among RBCs, ECs, and platelets plays a significant role in SCD, leading to vasoocclusive crisis and organ damage. These cells share biochemical properties relevant to SCD, such as high PNP levels and glycolytic metabolism. PNP activity and glycolysis promote RBC sickling/hemolysis, oxidative vascular injury, and platelet activation/aggregation in SCD.
Under hemolytic conditions, there is a significant interaction among red blood cells (RBCs), endothelial cells (ECs), and platelets in the injured vasculature. In sickle cell disease (SCD), this interaction leads to painful vasoocclusive crisis and end organ damage, results in poor quality of life, and unacceptably short life expectancy. We propose that these cells share two biochemical properties that are highly relevant to SCD. First, per cell volume, RBCs have the highest level of purine nucleoside phosphorylase (PNP, a key enzyme in purine metabolism), and ECs and platelets are very rich in PNP. Second, RBCs have to, ECs choose to, and platelets, when activated, switch to using glycolysis as a major pathway for intermediate phosphates and ATP production. We propose that these similarities are highly relevant to sickle cell disease (SCD) and hemolytic vascular injury. Human PNP catalyzes the phosphorolysis of guanosine/ deoxyguanosine and inosine /deoxyinosine into guanine and hypoxanthine, respectively, and generates ribose-1-phosphate and deoxyribose-1-phosphate. This results in forming a large amount of downstream pro-oxidant and vasculotoxic xanthines. Recently, we have detected that in SCD, hemolysis is associated with increased activity of extracellular PNP, accelerated guanosine and inosine metabolism, and augmented extracellular production of vasculotoxic hypoxanthine and xanthine. We identify PNP as a critical pathogenic mechanism in SCD and have proposed a link between PNP activity and the glycolytic production of intermediate phosphates and ATP. This link promotes (i) RBC sickling/hemolysis, (ii.) hemolytic angioproliferation, (iii.) oxidative vascular injury, and (iv.) platelets activation/aggregation. Furthermore, PNP accelerates guanosine/inosine metabolism and may diminish their well-documented antiinflammatory, anti-ischemic, anti-thrombotic, and anti-nociceptive effects. We hypothesize that inhibition of PNP may lessen those four (i.to iv.) deleterious events and may potentiate the beneficial effects of guanosine/ inosine, reducing the risk of vaso-occlusion and organ damage in SCD patients. Thereby, the PNP inhibitors may serve as a multipronged treatment approach for SCD.
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