In vivo rates of erythrocyte glutathione synthesis in adults with sickle cell disease

Reid, Marvin; Badaloo, Asha; Forrester, Terrence; Jahoor, Farook

doi:10.1152/ajpendo.00287.2005

Cited by 70 publications

(61 citation statements)

References 42 publications

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“…Our findings are consistent with other studies suggesting that lower erythrocyte GSH in SCD patients is not reflective of reduced substrate availability or decreased synthesis, but rather increased GSH consumption. 13,75 Glutathione depletion has long been known to occur in the plasma and erythrocytes of SCD patients. 14,15,17,18,32,75 By evaluating Figure 2.…”

Section: Discussionmentioning

confidence: 99%

“…Cellular GSH concentrations are significantly reduced in response to protein malnutrition, oxidative stress, aging, and many pathologic conditions, 1,10 including sickle cell disease (SCD), 13-18 a hemoglobinopathy associated with vasoocclusive and hemolytic complications. [19][20][21][22][23][24][25][26] Sickle erythrocytes have a shortened survival time and are more susceptible to oxidant damage than red blood cells from healthy individuals.…”

Section: Introductionmentioning

confidence: 99%

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Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease

Morris¹,

Suh²,

Hagar³

et al. 2008

Blood

167

143

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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. IntroductionThe erythrocyte redox environment may contribute to the increased oxidative stress, hemolysis, and decreased nitric oxide (NO) bioavailability observed in pulmonary hypertension (PH), a common complication of hemolytic disorders. Reduced glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular weight thiol 1 and the principal thiol redox buffer in erythrocytes. 2,3 The red blood cell contributes up to 10% of whole-body GSH synthesis in humans. [4][5][6] In addition to its role as a critical antioxidant, GSH possesses diverse biological functions involved in detoxification, cell proliferation and apoptosis, redox signaling, gene expression, protein glutathionylation, cytokine production, the immune response, mitochondrial function, and integrity as well as NO metabolism. 7,8 Glutathione is synthesized from glutamate, cysteine, and glycine via reactions catalyzed by 2 cytosolic enzymes, gammaglutamylcysteine ligase and GSH synthetase. The intracellular GSH concentration is the final result of a dynamic balance between the rate of GSH synthesis and the combined rate of intracellular GSH consumption and efflux. GSH is readily oxidized to glutathione disulfide (GSSG) by free radicals and reactive oxygen and nitrogen species. GSSG efflux from cells contributes to a net loss of intracellular GSH. 1 Due to its high intracellular concentrations, GSH variations in oxidation states can significantly modify the redox environment of red blood cells. Within the erythrocyte, GSH may...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease

Morris¹,

Suh²,

Hagar³

et al. 2008

Blood

167

143

View full text Add to dashboard Cite

show abstract

“…This process can contribute to vascular dysfunction, hemolysis, and a pro-thrombotic state. 32 Finally, alterations in the glutathione buffering system common to these hemoglobinopathies 30,33 may render erythrocytes incapable of handling the increased oxidant burden, thereby predisposing them to hemolysis. Recently we discovered that a depletion of erythrocyte glutamine concentration and aberrations in erythrocyte glutathione metabolism is linked to severity of PH in SCD and biomarkers of hemolytic rate.…”

Section: Oxidative Stressmentioning

confidence: 99%

Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia

Morris¹

2008

Hematology

166

214

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Many mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD), with dysfunction of the vascular endothelium as a unifying theme. Specifically, hemolysis-associated low arginine and nitric oxide (NO) bioavailability, amplified by NO synthase uncoupling, elevated arginase activity, superoxide production, oxidative stress, accumulation of arginine analogs such as asymmetric dimethylarginine, ischemia-reperfusion injury, inflammation, apolipoprotein A-1 depletion, and a hypercoagulable state are significant mechanisms contributing to endothelial dysfunction. Genetic polymorphisms also influence disease severity. Clearly the variable spectrum of disease is the consequence of multiple events and genetic susceptibility that go beyond the occurrence of a single amino acid substitution in the beta globin chain of hemoglobin. Recent studies begin to demonstrate overlap among these seemingly unrelated processes. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a common denominator in the pathogenesis of vasculopathy in SCD. The consequences of decreased NO bioavailability include endothelial cell activation, upregulation of the potent vasoconstrictor endothelin-1, vasoconstriction, platelet activation, increased tissue factor, and activation of coagulation, all of which ultimately translate into the clinical manifestations of SCD. Evidence supporting vasculopathy subphenotypes in SCD, including pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke, will be reviewed and relevance to other hemolytic disorders including the thalassemia syndromes will be considered.

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“…As expected, our experiments detected greater hemoglobin oxidation and lipid peroxidation in the erythrocytes of SS patients. A majority of studies on the SCD population have reported deficits in concentration of GSH (Hebbel et al, 1982;Wetterstroem, 1984;Hebbel, 1990;Hebbel, Leung, Mohandas, 1990;Aslan, Thornley-Brown, Freeman, 2000;Reid et al, 2006;Morris et al, 2008), while others have not found this pattern (Rice-Evans, Omorphos, Baysal, 1986;Somjee et al, 2004;Manfredini et al, 2008;Nur et al, 2011). Moreover, the GSSG (oxidized glutathione)/ GSH index was significantly elevated in SCD patients, supporting an important role for oxidative damage in these cells (Morris et al, 2008;Rusanova, 2010).…”

Section: Discussionmentioning

confidence: 99%

Ginkgo biloba extract (EGb 761) attenuates oxidative stress induction in erythrocytes of sickle cell disease patients

Furman

Henneberg

Hermann

et al. 2012

Braz. J. Pharm. Sci.

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Sickle cell disease promotes hemolytic anemia and occlusion of small blood vessels due to the presence of high concentrations of hemoglobin S, resulting in increased production of reactive oxygen species and decreased antioxidant defense capacity. The aim of this study was to evaluate the protective action of a standardized extract of Ginkgo biloba (EGb 761), selected due to its high content of flavonoids and terpenoids, in erythrocytes of patients with sickle cell anemia (HbSS, SS erythrocytes) subjected to oxidative stress using tert-butylhydroperoxide or 2,2-azobis-(amidinepropane)-dihydrochloride, in vitro. Hemolysis indexes, reduced glutathione, methemoglobin concentrations, lipid peroxidation, and intracellular reactive oxygen species were determined. SS erythrocytes displayed increased rates of oxidation of hemoglobin and membrane lipid peroxidation compared to normal erythrocytes (HbAA, AA erythrocytes), and the concentration of EGb 761 necessary to achieve the same antioxidant effect in SS erythrocytes was at least two times higher than in normal ones, inhibiting the formation of intracellular reactive oxygen species (IC50 of 13.6 µg/mL), partially preventing lipid peroxidation (IC50 of 242.5 µg/mL) and preventing hemolysis (IC50 of 10.5 µg/mL). Thus, EGb 761 has a beneficial effect on the oxidative status of SS erythrocytes. Moreover, EGb 761 failed to prevent oxidation of hemoglobin and reduced glutathione at the concentrations examined.

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In vivo rates of erythrocyte glutathione synthesis in adults with sickle cell disease

Cited by 70 publications

References 42 publications

Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease

Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease

Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia

Ginkgo biloba extract (EGb 761) attenuates oxidative stress induction in erythrocytes of sickle cell disease patients

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