Altered amount and activity of superoxide dismutase in sickle cell anemia

Schacter, Lee; Warth, James A.; Gordon, Erlinda M.; Prasad, Ananda S.; Klein, Bruce L.

doi:10.1096/fasebj.2.3.3350236

Cited by 50 publications

(33 citation statements)

References 24 publications

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“…manifestations had lower levels of SOD activity compared to those with milder symptoms but had the same amount of enzyme protein. Additionally, individuals with the sickle trait had amounts and activities of SOD comparable to black controls (Schacter et al, 1988).…”

Section: Discussionmentioning

confidence: 89%

“…This signal peptide is removed during processing to a mature enzyme and plays a key role in targeting the enzyme to the mitochondria. Oxidative stress plays a role in the pathophysiology of the clinical manifestations of the disease, and this may be contributory to the pathophysiology of the abnormalities that underlie the clinical course of SCA (Schacter et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ala-9Val polymorphism of Mn-SOD gene in sickle cell anemia

Söğüt¹,

Yönden²,

H³

et al. 2011

Genet. Mol. Res.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Ala-9Val polymorphism of Mn-SOD gene in sickle cell anemia

Söğüt¹,

Yönden²,

H³

et al. 2011

Genet. Mol. Res.

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“…29,35,50,51,[58][59][60][61][62][63] In hemolytic disorders such as SCD, the erythrocyte itself may be a major determinant of the global redox environment. It has been long established that sickle erythrocytes have increased concentrations of the reactive oxygen species compared with normal red blood cells.…”

Section: Discussionmentioning

confidence: 99%

“…[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. [27][28][29][30][31] Many of the alterations in the redox environment known to occur in SCD can impact global GSH homeostasis, including decreased enzymatic activity of glutathione peroxidase, 27,28 catalase 28 and GSH reductase, [15][16][17]32 impaired pentose phosphate shunt activity, 32 increased superoxide and free radical generation, 16,29,[33][34][35][36][37] decreased NO bioavailability, 20,21,23, [38][39][40][41][42][43][44][45] and decreased NAD redox potential. 46,47 Recently, erythrocyte GSH depletion has been linked to hemolysis, suggesting a direct role in erythrocyte viability.…”

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

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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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“…However, what is actually seen in SCD is a significantly lower antioxidative capacity in SCD erythrocytes, with reduced level of GSH 18,19 and decreased SOD, CAT, and GPX1 activities. 20,21 This reduced antioxidant capacity makes SCD erythrocytes especially susceptible to oxidative insult and hemolysis. 16,18,22 The basis for such reduced capacity to defend against oxidative stress in SCD is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease

Sangokoya

Telen

Chi³

2010

Blood

312

225

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Although individuals with homozygous sickle cell disease (HbSS) share the same genetic mutation, the severity and manifestations of this disease are extremely heterogeneous. We have previously shown that the microRNA expression in normal and HbSS erythrocytes exhibit dramatic differences. In this study, we identify a subset of HbSS patients with higher erythrocytic miR-144 expression and more severe anemia. HbSS erythrocytes are known to have reduced tolerance for oxidative stress, yet the basis for this phenotype remains unknown. This study reveals that miR-144 directly regulates nuclear factor-erythroid 2-related factor 2, a central regulator of cellular response to oxidative stress, and modulates the oxidative stress response in K562 cell line and primary erythroid progenitor cells. We further demonstrate that increased miR-144 is associated with reduced NRF2 levels in HbSS reticulocytes and with decreased glutathione regeneration and attenuated antioxidant capacity in HbSS erythrocytes, thereby providing a possible mechanism for the reduced oxidative stress tolerance and increased anemia severity seen in HbSS patients. IntroductionSickle cell disease (SCD) is a hemolytic anemia resulting from a single amino acid substitution in the ␤-globin gene that renders erythrocytes susceptible to intracellular hemoglobin polymerization in the deoxygenated state. Individuals homozygous for the sickle mutation (HbSS) have the most severe form of SCD, with acute and chronic sequelae. 1 Although many general principles of molecular genetics and cell biology have been established in SCD, its phenotypic heterogeneity and variable clinical severity has not been fully explained. Despite having the same HbS mutation, SCD patients display remarkably variable clinical courses in terms of incidence of painful events, severity of anemia, incidence of acute complications (such as stroke and acute chest syndrome), and frequency of end-organ damage (eg, heart disease, renal failure, leg ulcers, pulmonary hypertension). [2][3][4] The erythrocyte is a chief oxidative sink and important mobile detoxifying system in the human body. The effective antioxidant capacity of the red blood cell allows it to serve as an antioxidant for itself as well as other cells and tissues. In doing so, it is susceptible to hemolysis due to various contributors of oxidative stress. One central regulator of antioxidant response is nuclear factor-erythroid 2-related factor 2 (NRF2), a basic leucine zipper transcription factor. Under oxidative stress, NRF2 binds to the antioxidant response element (ARE), 5-8 found on the promoters of key genes involved in oxidative stress response. The binding of NRF2 to ARE is important for the coordinately inducible expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), GPX1, phase II detoxification enzymes such as NAD(P)H: quinone oxidoreductase (NQO1), and glutathione (GSH) synthesis and processing enzymes such as ␥-glutamylcysteine synthetase and GSH reductase. NRF2-regulated expression of AR...

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Altered amount and activity of superoxide dismutase in sickle cell anemia

Cited by 50 publications

References 24 publications

Ala-9Val polymorphism of Mn-SOD gene in sickle cell anemia

Ala-9Val polymorphism of Mn-SOD gene in sickle cell anemia

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

microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease

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