Journal
BLOOD
Volume 111, Issue 1, Pages 402-410Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-04-081703
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Funding
- NCRR NIH HHS [UL1 RR024131, UL1 RR024131-01] Funding Source: Medline
- NHLBI NIH HHS [HL-04386-05, K23 HL004386, K 23 HL079003-01, HL R01 68970, U54 HL070583, 1U54 HL 0708819, 1U54 HL070583] Funding Source: Medline
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR024131] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [K23HL079003, R01HL068970, T32HL007088, U54HL070583, K23HL004386] Funding Source: NIH RePORTER
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Erythrocyte glutathione depletion has been linked to hemolysis and oxidative stress. Glutamine plays an additional antioxidant role through preservation of intracellular nicotinamide adenine dinucleotide phosphate (NADPH) levels, required for glutathione recycling. Decreased nitric oxide (NO) bioavailability, which occurs in the setting of increased hemolysis and oxidative stress, contributes to the pathogenesis of pulmonary hypertension (PH) in sickle cell disease (SCD). We hypothesized that altered glutathione and glutamine metabolism play a role in this process. Total glutathione (and its precursors) and glutamine were assayed in plasma and erythrocytes of 40 SCD patients and 9 healthy volunteers. Erythrocyte total glutathione and glutamine levels were significantly lower in SCD patients than in healthy volunteers. Glutamine depletion was independently associated with PH, defined as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/s. The ratio of erythrocyte glutamine:glutamate correlated inversely to TRV (r = -0.62, P <.001), plasma arginase concentration (r = -0.45, P =.002), and plasma-free hemoglobin level (r = -0.41, P =.01), linking erythrocyte glutamine depletion to dysregulation of the arginine-NO pathway and increased hemolytic rate. Decreased erythrocyte glutathione and glutamine levels contribute to alterations in the erythrocyte redox environment, which may compromise erythrocyte integrity, contribute to hemolysis, and play a role in the pathogenesis of PH of SCD.
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