Hemoglobin redox reactions and oxidative stress

Rifkind, Joseph M.; Nagababu, Enika; Ramasamy, Somasundaram; Ravi, Luke B.

doi:10.1179/135100003225002817

Cited by 75 publications

(62 citation statements)

References 10 publications

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“…This is to be expected, as oxidative reactions in plasma are normally kept under tight control. 9,25,30,[43][44][45] In contrast, when plasma from sph/sph mice was tested, a dramatically higher amount of oxygen was consumed as a result of the oxidation of linoleic acid (Figure 4B filled bar; P Ͻ .013). This is most likely reflective of the increased levels of plasma free hemoglobin in sph/sph compared with ϩ/ϩ mice, and indicates that the plasma environment in sph/sph mice has a high oxidative potential.…”

Section: Increased Oxidizing Potential Of Plasma From Sph/sph Micementioning

confidence: 97%

“…9,10,[20][21][22][23][24][25] EPR studies, at liquid helium temperatures, show that there is not an increase in basal methemoglobin in plasma from sph/sph mice (Figure 4A open bars). These results may reflect the relatively short half-life of metHb in plasma.…”

Section: Increased Plasma Hemoglobin and No Scavenging Capacity In Spmentioning

confidence: 99%

“…10,[19][20][21][22][23] The rapid reaction between NO and oxygenated Hb (oxyHb) generates nitrate and methemoglobin (metHb). 19,20,24,25 Intravascular RBC hemolysis also results in the release of RBC arginase, which efficiently reacts with L-Arg to produce ornithine, thus scavenging the substrate for additional NO production by NO synthase. 9 Thus, bioavailable NO may be greatly reduced by intravascular hemolysis, contributing significantly to vascular dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Vascular dysfunction in a murine model of severe hemolysis

Frei

Guo

Jones

et al. 2008

Blood

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Spectrin is the backbone of the erythroid cytoskeleton; sph/sph mice have severe hereditary spherocytosis (HS) because of a mutation in the murine erythroid ␣-spectrin gene. sph/sph mice have a high incidence of thrombosis and infarction in multiple tissues, suggesting significant vascular dysfunction. In the current study, we provide evidence for both pulmonary and systemic vascular dysfunction in sph/sph mice. We found increased levels of soluble cell adhesion molecules in sph/ sph mice, suggesting activation of the vascular endothelium. We hypothesized that plasma hemoglobin released by intravascular hemolysis initiates endothelial injury through nitric oxide (NO) scavenging and oxidative damage. Likewise, electron paramagnetic resonance spectroscopy showed that plasma hemoglobin is much greater in sph/sph mice. Moreover, plasma from sph/sph mice had significantly higher oxidative potential. Finally, xanthine oxidase, a potent superoxide generator, is decreased in subpopulations of liver hepatocytes and increased on liver endothelium in sph/sph mice. These results indicate that vasoregulation is abnormal, and NO-based vasoregulatory mechanisms particularly impaired, in sph/sph mice. Together, these data indicate that sph/sph mice with severe HS have increased plasma hemoglobin and NO scavenging capacity, likely contributing to aberrant vasoregulation and initiating oxidative damage. (Blood. 2008;112:398-405) IntroductionThe membrane skeleton, a multiprotein complex located just beneath the plasma membrane, provides the red blood cells (RBCs) with the mechanical strength and deformability required to withstand the high shear forces of the microcapillaries. Spectrin, a tetramer composed of ␣-and ␤-subunits, is the backbone of the erythroid membrane skeleton and is tethered to the membrane at 2 positions. Disruption of either spectrin or proteins involved in tethering spectrin to the RBC plasma membrane can result in the hemolytic anemia known as hereditary spherocytosis (HS) in both humans and mice. [1][2][3] We have shown that sph/sph mice have severe autosomal recessive HS because of a spontaneous single-base deletion in the murine erythroid ␣-spectrin gene, Spna1. 4 Although heterozygous (sph/ϩ) mice are phenotypically normal, the sph/sph RBC is extremely fragile, resulting in an RBC life span of approximately 1 day (normal is 48 days). 5 As a consequence, sph/sph mice have a very severe hemolytic anemia, with hematocrit values of 0.15 to 0.20 and compensatory reticulocytosis of 90% to 95%. 5 As a result of the severe hemolysis, sph/sph mice with severe HS develop multiorgan pathology in kidney, heart, liver, and spleen. 6,7 In addition, sph/sph mice develop thrombosis and infarction in multiple tissues, 6-8 suggesting significant vascular dysfunction.Recent studies of patients with hemolytic anemia have indicated that the incidence of pulmonary hypertension, as indicated by increased tricuspid regurgitant jet velocity (Ն 3.0 m/sec), is relatively high in patients with sickle cell disease (SCD), thalassemia,...

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Section: Increased Oxidizing Potential Of Plasma From Sph/sph Micementioning

confidence: 97%

Section: Increased Plasma Hemoglobin and No Scavenging Capacity In Spmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vascular dysfunction in a murine model of severe hemolysis

Frei

Guo

Jones

et al. 2008

Blood

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“…A variety of tolerable drugs can disrupt redox pathways, create artificial pathways to oxygen, or serve as terminal electron sinks. The exact concentrations and redox states of various forms of parasite Fe are controversial (reviewed in Egan et al 2002); however, even moderate dosage with pro-oxidative antimalarial drugs increases oxidized forms of Fe within erythrocytes (Alayash et al 2001;Baird et al 2003;Rifkind et al 2003; and see "Discussion").…”

Section: Introductionmentioning

confidence: 99%

Responsiveness of parasite Cys His proteases to iron redox

Lockwood

2006

Parasitol Res

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Plasmodium falciparum growth can be opposed in erythrocyte culture or in vivo by nonselective inhibitors of CysHis proteases or pro-oxidative drugs, which elevate erythrocyte Fe(3+). However, no relationship between Fe redox and CysHis protease inhibition has been suggested. Here, mature falcipain-2 was found to be inhibited by relevant concentrations of Fe(3+) but not Fe(2+) in the presence of excess GSH or DTT. Initial inhibition of falcipain-2 by Fe(3+) (1-50 microM) was reversed in temporal correlation with the 12-14 min half-time of Fe(3+) reduction to Fe(2+) caused by GSH or DTT (6 mM). The metal-redox responses of cathepsin B from mammal, cruzain from Trypanosoma cruzi, and falcipain-2 from P. falciparum were similar. Fe(3+)/Fe(2+) speciation has features consistent with a natural redox switch modifying the reaction rate of mature CysHis proteases in virtually all cell types. Pro-oxidative antimalarial therapy might intervene in a natural mechanism normally modifying CysHis protease reaction rates via redox state of Fe pools.

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“…Both element oxygen and iron are able to quickly shift their oxidative state in response to different emerging stimuli. Literature shows in [1] that hemoglobin may undergo oxidative reaction in the process of releasing oxygen. In this process iron is oxidized to Fe 3+ and reactive oxygen species are generated.…”

Section: Red Blood Cells Oxidative-reducing Balancementioning

confidence: 99%