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Blood, 1 January 2008, Vol. 111, No. 1, pp. 402-410.
Prepublished online as a Blood First Edition Paper on September 11, 2007; DOI 10.1182/blood-2007-04-081703.
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Submitted April 10, 2007
Accepted September 4, 2007
Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease
Claudia R. Morris*, Jung H Suh, Ward Hagar, Sandra Larkin, D. Anton Bland, Martin H Steinberg, Elliott P. Vichinsky, Mark Shigenaga, Bruce Ames, Frans A. Kuypers, and Elizabeth S. Klings
Department of Emergency Medicine, Children's Hospital & Research Center Oakland, Oakland, CA, United States
Children's Hospital Oakland Research Institute, Oakland, CA, United States
Department of Hematology-Oncology, Children's Hospital & Research Center Oakland, Oakland, CA, United States
The Pulmonary Center, Boston University School of Medicine, Boston, MA, United States
Department of Medicine, Boston Comprehensive Sickle Cell Center, Boston University School of Medicine, Boston, MA, United States
* Corresponding author; email: claudiamorris{at}comcast.net.
Erythrocyte glutathione depletion has been linked to hemolysis and oxidative stress. Glutamine plays an additional anti-oxidant 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 may 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 normal volunteers. Erythrocyte total glutathione and glutamine levels were significantly lower in SCD patients than normal volunteers. Glutamine depletion was independently associated with PH, defined as a tricuspid regurgitant jet velocity (TRV)  2.5 m/s. The ratio of erythrocyte glutamine:glutamate correlated inversely to TRV (r= -0.62, p<0.0001), plasma arginase concentration (r= -0.45, p=0.002 ), and plasma-free hemoglobin level (r= -0.41, p=0.01), 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 and play a role in the pathogenesis of PH of SCD.
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