Covalent binding of glutathione to hemoglobin. I. Inhibition of hemoglobin S polymerization.

Garel, Marie-Claude; Domenget, Chantal; Caburi-Martin, Josiane; Préhu, Claude; Galactéros, Frédéric; Beuzard, Yves

doi:10.1016/s0021-9258(18)66928-5

Cited by 97 publications

(25 citation statements)

References 44 publications

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“…The process depends on GSH and GSSG concentration and is a radical-mediated process. In SCD RBCs, HbS can undergo to glutathionylation, which increases the oxygen affinity, reduces the heme-heme interactions and inhibits the sickling protein [141].…”

Section: Antioxidant Defenses In Scdmentioning

confidence: 99%

Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

et al. 2021

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Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

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Section: Antioxidant Defenses In Scdmentioning

confidence: 99%

Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

et al. 2021

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“…Based on a previous report on GSH-mediated attenuation of hemeinduced adhesion molecule expression in ECs, 29 we surmised that the GSH level may be upregulated in SCD::Keap1F/F::LysM-Cre mice. To address this hypothesis, we examined the GSH distribution with iMScope and found that the signal intensity of GSH (m/z 306.07) was significantly stronger in SCD::Keap1F/F::LysM-Cre mice than in SCD::Keap1F/F mice (Figure 2Ei-ii).…”

Section: Nrf2 Activation In Monocytes/granulocytes Ameliorates Organ Damage In Scd Micementioning

confidence: 99%

Nrf2 activation in myeloid cells and endothelial cells differentially mitigates sickle cell disease pathology in mice

Keleku-Lukwete¹,

Suzuki

Panda³

et al. 2019

Blood Advances

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Sickle cell disease (SCD) is caused by a monogenic mutation of the β-globin gene and affects millions of people worldwide. SCD is associated with sustained hemolytic anemia, vasoocclusion, ischemia-reperfusion injury, oxidative tissue damage, inflammatory cell activation, and systemic endothelial dysfunction. The transcription factor Nrf2 coordinates the expression of a wide variety of genes encoding antioxidant, detoxification, and metabolic enzymes. Nrf2 participates in suppressing proinflammatory cytokines and organ protection in SCD. However, little is known regarding the mechanisms by which Nrf2 ameliorates SCD pathology or how some cells respond to Nrf2 stimuli to alleviate SCD pathology. Here, we asked whether monocytes/granulocytes and/or endothelial cells are particularly critical in alleviating the pathology of SCD. By targeting these cells with a Cre recombinase system, we generated SCD::Keap1F/F::LysM-Cre and Tie1-Cre mice with constitutive Nrf2 activation in monocytes/granulocytes and endothelial cells, respectively. Analyses of SCD::Keap1F/F::LysM-Cre and SCD::Keap1F/F::Tie1-Cre mice revealed significantly reduced inflammation, along with decreased white blood cell counts and lower Tnfα and Il1β expression in the lungs. Notably, SCD::Keap1F/F::LysM-Cre mice exhibited reduced heme distribution in the liver, consistent with a decrease in the damaged areas. Vascular function in SCD::Keap1F/F::Tie1-Cre mice was significantly improved, with a 50% decrease in vascular leakage and low expression of the adhesion molecules Vcam1 and P-selectin. Thus, Nrf2 activation in monocytes/granulocytes and endothelial cells contributes differentially and cooperatively to the improvement of SCD pathology.

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“…Glutathionylated human hemoglobin (HbSSG) is a minor form of hemoglobin that carries a glutathione (γECG) linked through a disulfide (R 1 CS-SCR 2 ) bond to the thiol group of a cysteine residue, mainly characterized as the β- 93 C in a single beta-chain of the tetramer. This form of hemoglobin was first highlighted in 1962 [ 1 ] and further characterized in 1986 [ 2 , 3 , 4 ] as a form that inhibits the polymerization of the sickle-cell Hb-S mutated form.…”

Section: Introductionmentioning

confidence: 99%

The Redox Potential of the β-93-Cysteine Thiol Group in Human Hemoglobin Estimated from In Vitro Oxidant Challenge Experiments

Rubino¹

2021

Molecules

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Glutathionyl hemoglobin is a minor form of hemoglobin with intriguing properties. The measurement of the redox potential of its reactive β-93-Cysteine is useful to improve understanding of the response of erythrocytes to transient and chronic conditions of oxidative stress, where the level of glutathionyl hemoglobin is increased. An independent literature experiment describes the recovery of human erythrocytes exposed to an oxidant burst by measuring glutathione, glutathione disulfide and glutathionyl hemoglobin in a two-hour period. This article calculates a value for the redox potential E0 of the β-93-Cysteine, considering the erythrocyte as a closed system at equilibrium described by the Nernst equation and using the measurements of the literature experiment. The obtained value of E0 of −121 mV at pH 7.4 places hemoglobin as the most oxidizing thiol of the erythrocyte. By using as synthetic indicators of the concentrations the electrochemical potentials of the two main redox pairs in the erythrocytes, those of glutathione–glutathione disulfide and of glutathionyl–hemoglobin, the mechanism of the recovery phase can be hypothesized. Hemoglobin acts as the redox buffer that scavenges oxidized glutathione in the oxidative phase and releases it in the recovery phase, by acting as the substrate of the NAD(P)H-cofactored enzymes.

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Covalent binding of glutathione to hemoglobin. I. Inhibition of hemoglobin S polymerization.

Cited by 97 publications

References 44 publications

Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Nrf2 activation in myeloid cells and endothelial cells differentially mitigates sickle cell disease pathology in mice

The Redox Potential of the β-93-Cysteine Thiol Group in Human Hemoglobin Estimated from In Vitro Oxidant Challenge Experiments

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