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Review
. 2015 Dec:6:226-239.
doi: 10.1016/j.redox.2015.07.018. Epub 2015 Aug 1.

Oxidative stress in β-thalassaemia and sickle cell disease

S Voskou  1 , M Aslan  2 , P Fanis  1 , M Phylactides  3 , M Kleanthous  1
Affiliations
Review

Oxidative stress in β-thalassaemia and sickle cell disease

S Voskou et al. Redox Biol. 2015 Dec.

Abstract

Sickle cell disease and β-thalassaemia are inherited haemoglobinopathies resulting in structural and quantitative changes in the β-globin chain. These changes lead to instability of the generated haemoglobin or to globin chain imbalance, which in turn impact the oxidative environment both intracellularly and extracellularly. The ensuing oxidative stress and the inability of the body to adequately overcome it are, to a large extent, responsible for the pathophysiology of these diseases. This article provides an overview of the main players and control mechanisms involved in the establishment of oxidative stress in these haemoglobinopathies.

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Graphical abstract
Fig. 2
Fig. 2
Oxidative events in the bone marrow and circulation. (1) Erythroid expansion. (2) Ineffective erythropoiesis. (3) Endocytosis of RBCs by macrophages through two different mechanisms: eryptosis and senescence. (4) Haemolysis. It leads to Hb release in the plasma, which subsequently autoxidises producing ROS, free haeme and iron. (5) ROS, free haeme and iron intercalate into plasma membranes producing oxidative damage to the endothelium and haematopoietic cells. ROS and haeme activate NF-κB and AP-1, which increase the production of pro-inflammatory cytokines (IL-1, IL-6, TNFα) and adhesion molecules on the endothelium. This increases the adhesion of RBCs, leucocytes and platelets to the endothelium. Activated leucocytes generate more ROS by their NADPH oxidase, creating a vicious cycle of oxidative stress and inflammation. (6) Reduction of NO bioavailability due to free Hb, ROS, and neutrophil activation, (7) Increased expression of plasma and endothelial enzymes (e.g. xanthine oxidase, NADPH oxidase and iNOS) following I/R gives rise to more ROS.
Fig. 1
Fig. 1
(A) Intracellular oxidative events. (1) Oxidative denaturation of Hb. It results in the production of ROS, free haeme and iron. Iron acts as a Fenton reagent in the Haber–Weiss reaction for the generation of hydroxyl radical. Haeme promotes oxidation reactions and a proinflammatory effect by activating NF-κB. (2) Enzymatic generation of superoxide by NADPH oxidase. NADPH oxidase is regulated by intra- (e.g. increased Ca2+) and extra-cellular (pro-inflammatory cytokines) signals that are activated by ROS. (3) ROS and ROS-induced increase of intra-cellular Ca2+ activate caspase-3, which partially degrades band-3, affecting its interaction with the cytoskeleton. ROS and increased Ca2+ also activate the KCC and Gardos channel respectively, resulting in increased exit of K+ from the cell. (4) Haemichromes mediate the oxidative crosslinking and phosphorylation of band-3 leading to band-3 clusterisation and dissociation from cytoskeletal proteins. This results in membrane blebbing and microparticle generation. Band-3/haemachrome clusters are recognised by anti-band-3-NAbs. (5) ROS promote oxidation of protein 4.1, actin and spectrin resulting in impaired interaction. (6) PS exposure results from ROS-induced disruption of normal membrane organisation. (B) Protective mechanisms in RBCs and the circulation. (1) Haptoglobin/Hb and haemopexin/haeme complexes are endocytosed by macrophages. Haeme is then degraded by HO-1 releasing biliverdin, CO and iron. Iron is then taken up by ferritin. (2) Antioxidant enzymes and molecules in RBCs. (3) Stress-response mechanisms in RBCs. FOXO3, HRI/eIF2α/ATF4 and NRF2 are oxidant-response pathways that regulate the expression of antioxidant genes. FOXO3 and HRI/eIF2α/ATF4 are important for terminal differentiation. PRDX2 is a chaperone of Hb and binds free haeme to prevent its oxidative actions. AHSP binds α-globin in the absence of β-globin and in the presence of oxidant insults. (4) Protein quality control pathways. Unpaired α-globins are selectively degraded via ubiquidin-mediated proteasomal degradation (UPS). When UPS becomes overwhelmed, α-globin aggregates are degraded via aggresome-mediated macroautophagy.
Fig. 3
Fig. 3
Scheme of intravascular nitric oxide consumption in sickle cell disease. Superoxide (O2•-) generated by uncoupled eNOS, xanthine oxidase, and NADPH oxidase reacts with NO to form peroxynitrite (ONOO−). Nitric oxide is also consumed by plasma free haemoglobin, released by intravascular haemolysis and myeloperoxidase (MPO). The reaction between MPO and hydrogen peroxide (H2O2) results in the formation of compound I (I), the two electron oxidised form of the enzyme. Compound I can either oxidise halides in a single two-electron step or can oxidise multiple substrates through sequential one electron steps, forming compound II. Tyrosine (Tyr) and ascorbate (Asc) are abundant substrates that can undergo one-electron oxidation by MPO-compound I, forming tyrosyl (•Tyr) and ascorbyl (•Asc) radicals. The reaction of nitric (•NO) with both tyrosyl and ascorbyl radicals is diffusion limited and leads to the catalytic consumption of •NO.
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References

    1. 〈http://www.webcitation.org/6a451MtZq〉
    1. Abraham E. NF-kappaB activation. Crit. Care Med. 2000;28:N100–104. - PubMed
    1. Adamsky K., Weizer O., Amariglio N., Breda L., Harmelin A., Rivella S., Rachmilewitz E., Rechavi G. Decreased hepcidin mRNA expression in thalassemic mice. Br. J. Haematol. 2004;124:123–124. - PubMed
    1. Aidoo M., Terlouw D.J., Kolczak M.S., McElroy P.D., ter Kuile F.O., Kariuki S., Nahlen B.L., Lal A.A., Udhayakumar V. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet. 2002;359:1311–1312. - PubMed
    1. Alam J., Killeen E., Gong P., Naquin R., Hu B., Stewart D., Ingelfinger J.R., Nath K.A. Heme activates the heme oxygenase-1 gene in renal epithelial cells by stabilizing Nrf2. Am. J. Physiol. Ren. Physiol. 2003;284:F743–752. - PubMed

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