Mouse α chains inhibit polymerization of hemoglobin induced by human or chains

Rhoda, Marie-Dominique; Domenget, Chantal; Vidaud, Michel; Bardakdjian‐Michau, Josiane; Rouyer-Fessard, P; Rosa, J.; Beuzard, Yves

doi:10.1016/0167-4838(88)90117-3

Cited by 32 publications

(14 citation statements)

References 17 publications

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“…The presence of γ or α mouse in heterotetramers may reduce the amount of membrane-associated, unstable β-chains. The low level of degradation products in NY1DD mice may, thus, be due to reduced polymer formation (the residual mouse α-chains inhibit polymer formation as efficiently as human γ) [26] or the more efficient interaction of murine α-globin with murine alpha Hb sparing protein (AHSP) [27]. Since NY1DD and NY1KO-γM mice have about the same percent β S , but very different levels of heme degradation products, we speculate that inefficient interaction of human α with murine AHSP may also contribute to the oxidative environment of murine RBCs that express exclusively human Hbs.…”

Section: Discussion Fluorescence In Pathological Rbcmentioning

confidence: 99%

Heme degradation and oxidative stress in murine models for hemoglobinopathies: Thalassemia, sickle cell disease and hemoglobin C disease

Nagababu

Fabry

Nagel

et al. 2008

Blood Cells, Molecules, and Diseases

102

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Red blood cells with abnormal hemoglobins (Hb) are frequently associated with increased hemoglobin autoxidation, accumulation of iron in membranes, increased membrane damage and a shorter red cell life span. The mechanisms for many of these changes have not been elucidated. We have shown in our previous studies that hydrogen peroxide formed in association with hemoglobin autoxidation reacts with hemoglobin and initiates a cascade of reactions that results in heme degradation with the formation of two fluorescent emission bands and the release of iron. Heme degradation was assessed by measuring the fluorescent band at ex 321 nm. A 5.6 fold increase in fluorescence was found in red cells from sickle transgenic mice that expressed exclusively human globins when compared to red cells from control mice. When sickle transgenic mice co-express the γM transgene, that expresses HbF and inhibits polymerization, heme degradation is decreased. Mice expressing exclusively hemoglobin C had a 6.9 fold increase in fluorescence compared to control. Heme degradation was also increased 3.5 fold in β-thalassemic mice generated by deletion of murine β major . Membrane bound IgG and red cell metHb were highly correlated with the intensity of the fluorescent heme degradation band. These results suggest that degradation of the heme moiety in intact hemoglobin and/or degradation of free heme by peroxides are higher in pathological RBCs. Concomitant release of iron appears to be responsible for the membrane damage that leads to IgG binding and the removal of red cells from circulation.

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Section: Discussion Fluorescence In Pathological Rbcmentioning

confidence: 99%

Heme degradation and oxidative stress in murine models for hemoglobinopathies: Thalassemia, sickle cell disease and hemoglobin C disease

Nagababu

Fabry

Nagel

et al. 2008

Blood Cells, Molecules, and Diseases

102

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“…Mice expressing "super-␤ S " have been particularly informative about the effect of the sicklable red cell on the pathophysiology of the mouse and mouse red cells (5)(6)(7)(11)(12)(13). All of these mice express residual levels of mouse globins which interfere with polymer formation (14) and may preferentially combine with human globin chains (15). The presence of mouse globins is a particular complication in the interpretation of results of gene therapy protocols where an antisickling hemoglobin is introduced.…”

Section: Introductionmentioning

confidence: 99%

Magnetic resonance evidence of hypoxia in a homozygous alpha-knockout of a transgenic mouse model for sickle cell disease.

Fabry¹,

Kennan²,

Pàszty³

et al. 1996

J. Clin. Invest.

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All transgenic mouse models for sickle cell disease express residual levels of mouse globins which complicate the interpretation of experimental results. We now report on a mouse expressing high levels of human ␤ S and 100% human ␣ -globin. These mice were created by breeding the ␣ -knockout and the mouse ␤ major -deletion to homozygosity in mice expressing human ␣ -and ␤ S -transgenes. These ␤ S -␣ -knockout mice have accelerated red cell destruction, altered hematological indices, ongoing organ damage, and pathology under ambient conditions which are comparable with those found in

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“…1 Introduction of human ␣-globin and deletion of the mouse ␤ major2-5 increased intracellular polymer formation. 6 Another advance was the introduction of dominant sickle globin genes: ␤ S-Antilles7 or the recombinant construct ␤ SAD .…”

Section: Introductionmentioning

confidence: 99%

“…6 Another advance was the introduction of dominant sickle globin genes: ␤ S-Antilles7 or the recombinant construct ␤ SAD . [8][9][10][11] However, mouse globins and supersickling globins can greatly complicate the interpretation of the effect of antisickling globins proposed for use in gene therapy by: (1) requiring mouse ␣, which is an antisickling globin, 1,12 for viability; (2) introducing a high or low oxygen affinity that alters the probability that ␤ S will deoxygenate and form polymer at venous pO 2; and (3) altering the nucleation process that can affect the delay time and affect probability of vaso-occlusion. 8 Hence, mice expressing exclusively human ␣ and ␤ S are a desirable starting point for testing antisickling strategies.…”

Section: Introductionmentioning

confidence: 99%

Second generation knockout sickle mice: the effect of HbF

Fabry

Suzuka

Weinberg

et al. 2001

Blood

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Sickle transgenic mice expressing exclusively human globins are desirable for studying pathophysiology and testing gene therapy strategies, but they must have significant pathology and show evidence of amelioration by antisickling hemoglobins. Mice were generated that expressed exclusively human sickle hemoglobin with 3 levels of HbF using their previously described sickle constructs (cointegrated human miniLCR␣2 and miniLCR␤ S [PNAS 89:12150, 1992]), mouse ␣-and ␤-globin-knockouts, and 3 different human ␥-transgenes. It was found that, at all 3 levels of HbF expression, these mice have balanced chain synthesis, nearly normal mean corpuscular hemoglobin, and, in some cases, F cells. Mice with the least adult HbF expression were the most severe. Progressive increase in HbF from less than 3% to 20% to 40% correlated with progressive increase in hematocrit (22% to 34% to 40%) and progressive decrease in reticulocyte count (from 60% to 30% to 13%). Urine concentrating ability was normalized at high HbF, and tissue damage detected by histopathology and organ weight were ameliorated by increased HbF. The ␥-transgene that produces intermediate levels of HbF was introduced into knockout sickle mice described by Pàszty and coworkers that express the miniLCR␣1 G

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Mouse α chains inhibit polymerization of hemoglobin induced by human or chains

Cited by 32 publications

References 17 publications

Heme degradation and oxidative stress in murine models for hemoglobinopathies: Thalassemia, sickle cell disease and hemoglobin C disease

Heme degradation and oxidative stress in murine models for hemoglobinopathies: Thalassemia, sickle cell disease and hemoglobin C disease

Magnetic resonance evidence of hypoxia in a homozygous alpha-knockout of a transgenic mouse model for sickle cell disease.

Second generation knockout sickle mice: the effect of HbF

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