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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. This Article Full Text Full Text (PDF) Supplemental Methods and Table All Versions of this Article: blood-2007-04-081703v1 111/1/402    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Morris, C. R. Articles by Klings, E. S. Search for Related Content PubMed PubMed Citation Articles by Morris, C. R. Articles by Klings, E. S. Related Collections Clinical Trials and Observations Red Cells Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease Claudia R. Morris1, Jung H. Suh2, Ward Hagar3, Sandra Larkin2, D. Anton Bland4, Martin H. Steinberg5, Elliott P. Vichinsky3, Mark Shigenaga2, Bruce Ames2, Frans A. Kuypers2, and Elizabeth S. Klings4,5 1 Department of Emergency Medicine, Children's Hospital and Research Center Oakland, CA; 2 Children's Hospital Oakland Research Institute, CA; 3 Department of Hematology/Oncology, Children's Hospital and Research Center Oakland, CA; 4 The Pulmonary Center, Boston University School of Medicine, MA; and 5 Boston Comprehensive Sickle Cell Center, Department of Medicine, Boston University School of Medicine, MA 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Amino acids and the erythrocyte under stress? Roberto F. Machado Blood 2008 111: 2. [Full Text] [PDF] This article has been cited by other articles: M. L. Krajewski, L. L. Hsu, and M. T. Gladwin The proverbial chicken or the egg? Dissection of the role of cell-free hemoglobin versus reactive oxygen species in sickle cell pathophysiology Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H4 - H7. [Full Text] [PDF] M. Tiso, A. Strub, C. Hesslinger, C. T. Kenney, R. Boer, and D. J. Stuehr BYK191023 (2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine) Is an NADPH- and Time-Dependent Irreversible Inhibitor of Inducible Nitric-Oxide Synthase Mol. Pharmacol., April 1, 2008; 73(4): 1244 - 1253. [Abstract] [Full Text] [PDF]

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