scholarly journals Characterization and comparison of the red blood cell membrane damage in severe human alpha- and beta-thalassemia

Blood ◽  
1992 ◽  
Vol 79 (4) ◽  
pp. 1058-1063 ◽  
Author(s):  
R Advani ◽  
S Sorenson ◽  
E Shinar ◽  
W Lande ◽  
E Rachmilewitz ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Membrane Damage ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Cell Membrane Damage ◽  
Protein 4.1 ◽  
Globin Chains ◽  
Alpha Thalassemia ◽  
Alpha Globin

Abstract The aim of the present work was to understand the pathophysiology of the severe human thalassemias as represented by beta-thalassemia intermedia and hemoglobin (Hb) H (alpha-thalassemia) disease. We have previously shown that the material properties of the red blood cell (RBC) and its membrane differ in severe alpha- and beta-thalassemia, and we now show that this difference is probably caused by accumulation of alpha-globin chains at the cytoskeleton in beta-thalassemia, whereas beta-globin chains are associated with the cytoskeleton in alpha- thalassemia. In both alpha- and beta-thalassemia, some of these globin chains have become oxidized as evidenced by loss of the free thiols. Furthermore, there is similar evidence of oxidation of protein 4.1 in beta-thalassemia, whereas beta-spectrin appears to be subject to oxidation in alpha-thalassemia. These observations support the idea that the association of partly oxidized globin chains with the cytoskeleton results in oxidation of adjacent skeletal proteins. The abnormality of protein 4.1 in beta-thalassemia is consistent with a prior observation, and is also in accord with the known importance of protein 4.1 in maintenance of membrane stability, a property that is abnormal in beta-thalassemic membranes.

scholarly journals Characterization and comparison of the red blood cell membrane damage in severe human alpha- and beta-thalassemia

Blood ◽  
1992 ◽  
Vol 79 (4) ◽  
pp. 1058-1063 ◽  
Author(s):  
R Advani ◽  
S Sorenson ◽  
E Shinar ◽  
W Lande ◽  
E Rachmilewitz ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Membrane Damage ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Cell Membrane Damage ◽  
Protein 4.1 ◽  
Globin Chains ◽  
Alpha Thalassemia ◽  
Alpha Globin

The aim of the present work was to understand the pathophysiology of the severe human thalassemias as represented by beta-thalassemia intermedia and hemoglobin (Hb) H (alpha-thalassemia) disease. We have previously shown that the material properties of the red blood cell (RBC) and its membrane differ in severe alpha- and beta-thalassemia, and we now show that this difference is probably caused by accumulation of alpha-globin chains at the cytoskeleton in beta-thalassemia, whereas beta-globin chains are associated with the cytoskeleton in alpha- thalassemia. In both alpha- and beta-thalassemia, some of these globin chains have become oxidized as evidenced by loss of the free thiols. Furthermore, there is similar evidence of oxidation of protein 4.1 in beta-thalassemia, whereas beta-spectrin appears to be subject to oxidation in alpha-thalassemia. These observations support the idea that the association of partly oxidized globin chains with the cytoskeleton results in oxidation of adjacent skeletal proteins. The abnormality of protein 4.1 in beta-thalassemia is consistent with a prior observation, and is also in accord with the known importance of protein 4.1 in maintenance of membrane stability, a property that is abnormal in beta-thalassemic membranes.

scholarly journals Globin-chain specificity of oxidation-induced changes in red blood cell membrane properties

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1586-1592 ◽  
Author(s):  
SL Schrier ◽  
N Mohandas
Keyword(s):  
Membrane Damage ◽  
Membrane Skeleton ◽  
Material Behavior ◽  
Membrane Properties ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Globin Chain ◽  
Globin Chains ◽  
Alpha Globin

Abstract We have previously shown that excess unpaired alpha- and beta-globin chains in severe alpha- and beta-thalassemia interacting with the membrane skeleton induce different changes in membrane properties of red blood cells (RBCs) in these two phenotypes. We suggest that these differences in membrane material behavior may reflect the specificity of the membrane damage induced by alpha- and beta-globin chains. To further explore this hypothesis, we sought in vitro models that induce similar membrane alterations in normal RBCs. We found that treatment of normal RBCs with phenylhydrazine produced rigid and mechanically unstable membranes in conjunction with selective association of oxidized alpha-globin chains with the membrane skeleton, features characteristic of RBCs in severe beta-thalassemia. Methylhydrazine, in contrast, induced selective association of oxidized beta-globin chains with the membrane skeleton and produced rigid but hyperstable membranes, features that mimicked those of RBCs in severe alpha- thalassemia. These findings suggest that consequences of oxidation induced by globin chains are quite specific in that those agents that cause alpha-globin chain accumulation at the membrane produce rigid but mechanically unstable membranes, whereas membrane accumulation of beta- globin chains results in rigid but mechanically stable membranes. These in vitro experiments lend further support to the hypothesis that membrane-associated alpha- and beta-chains induce oxidative damage to highly specific different skeletal components and that the specificity of this skeletal damage accounts for the differences in material membrane properties of these oxidatively attacked RBCs and perhaps of alpha- and beta-thalassemic RBCs as well.

scholarly journals Globin-chain specificity of oxidation-induced changes in red blood cell membrane properties

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1586-1592 ◽  
Author(s):  
SL Schrier ◽  
N Mohandas
Keyword(s):  
Membrane Damage ◽  
Membrane Skeleton ◽  
Material Behavior ◽  
Membrane Properties ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Globin Chain ◽  
Globin Chains ◽  
Alpha Globin

We have previously shown that excess unpaired alpha- and beta-globin chains in severe alpha- and beta-thalassemia interacting with the membrane skeleton induce different changes in membrane properties of red blood cells (RBCs) in these two phenotypes. We suggest that these differences in membrane material behavior may reflect the specificity of the membrane damage induced by alpha- and beta-globin chains. To further explore this hypothesis, we sought in vitro models that induce similar membrane alterations in normal RBCs. We found that treatment of normal RBCs with phenylhydrazine produced rigid and mechanically unstable membranes in conjunction with selective association of oxidized alpha-globin chains with the membrane skeleton, features characteristic of RBCs in severe beta-thalassemia. Methylhydrazine, in contrast, induced selective association of oxidized beta-globin chains with the membrane skeleton and produced rigid but hyperstable membranes, features that mimicked those of RBCs in severe alpha- thalassemia. These findings suggest that consequences of oxidation induced by globin chains are quite specific in that those agents that cause alpha-globin chain accumulation at the membrane produce rigid but mechanically unstable membranes, whereas membrane accumulation of beta- globin chains results in rigid but mechanically stable membranes. These in vitro experiments lend further support to the hypothesis that membrane-associated alpha- and beta-chains induce oxidative damage to highly specific different skeletal components and that the specificity of this skeletal damage accounts for the differences in material membrane properties of these oxidatively attacked RBCs and perhaps of alpha- and beta-thalassemic RBCs as well.

scholarly journals Oxidative red blood cell membrane injury in the pathophysiology of severe mouse beta-thalassemia

Blood ◽  
1992 ◽  
Vol 79 (4) ◽  
pp. 1064-1067 ◽  
Author(s):  
R Advani ◽  
E Rubin ◽  
N Mohandas ◽  
SL Schrier
Keyword(s):  
Transgenic Mice ◽  
Blood Cell ◽  
Transgenic Mouse ◽  
Red Blood Cell ◽  
Mechanical Stability ◽  
Clinical Status ◽  
Beta Thalassemia ◽  
Membrane Injury ◽  
Protein 4.1 ◽  
Alpha Globin

In severe human beta-thalassemia, the pathophysiology relates to accumulation of excess alpha-globin chains at the membrane. One hypothesis is that membrane-associated alpha-globin by virtue of it's iron or hemichromes produces oxidation of adjacent membrane proteins. The availability of a mouse model of severe beta-thalassemia, as well as a transgenic (thalassemic-sickle) mouse that expresses 12% of human beta s-chain, has allowed us to study the effect of graded accumulation of alpha-chains at the red blood cell (RBC) membrane on the clinical status of the animal and on the material properties of its RBCs. Proteins from control, beta-thalassemic, and transgenic mouse RBC membranes were analyzed for evidence of oxidation, as measured by thiol- disulfide exchange chromatography, which detects intramolecular sulfhydryl oxidation. Ratios of oxidized globin to protein 7 were calculated and increased amounts were seen in thalassemic mice as compared with control mice and transgenic mice. Furthermore, there were increased amounts of thiol-free protein 4.1 in the thalassemic mice, compared with very small amounts in the control mice and intermediate amounts in the transgenic mice. Membrane mechanical stability as assessed by ektacytometry showed that the thalassemic mouse RBCs were markedly unstable. Transgenic mouse RBCs showed intermediate levels of membrane instability compared with the controls. We propose that this oxidized globin, in conjunction with oxidized protein 4.1, accounts (at least in part) for membrane instability. A 12% increase in beta s- globin chain synthesis (by decreasing excess globin available) confers considerable protection against both oxidative damage and the consequent membrane instability.

scholarly journals The role of membrane skeletal-associated alpha-globin in the pathophysiology of beta-thalassemia

Blood ◽  
1990 ◽  
Vol 75 (6) ◽  
pp. 1333-1336 ◽  
Author(s):  
S Sorensen ◽  
E Rubin ◽  
H Polster ◽  
N Mohandas ◽  
S Schrier
Keyword(s):  
Transgenic Mice ◽  
Blood Cell ◽  
Red Blood Cells ◽  
Red Blood Cell ◽  
Blood Cells ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Cell Deformability ◽  
Red Blood Cell Deformability ◽  
Alpha Globin

The beta-thalassemic mouse provides a useful model for testing hypotheses about the pathophysiology in human beta-thalassemia. The clinical picture of these mice and their red blood cell deformability characteristics are quite similar to those observed in human beta- thalassemia intermedia. The creation of transgenic mice that express human beta-globin (beta s) has provided an opportunity to study the effect of increasing the non-alpha-globin chain production on the thalassemic phenotype. A small increase in beta-globin production produces transgenic mice that are healthier, have almost normal hemoglobin values, and whose red blood cell deformability is increased. We quantified and characterized the membrane skeletal-associated globin in normal, transgenic thal/sickle, and thalassemic mice and showed that only alpha-globin was associated with the membrane skeleton in the pathologic red blood cells, and that the degree of rigidity as measured in the rheoscope correlated directly and closely with the amount of membrane skeletal-associated globin in these abnormal red blood cells.

scholarly journals Oxidative red blood cell membrane injury in the pathophysiology of severe mouse beta-thalassemia

Blood ◽  
1992 ◽  
Vol 79 (4) ◽  
pp. 1064-1067 ◽  
Author(s):  
R Advani ◽  
E Rubin ◽  
N Mohandas ◽  
SL Schrier
Keyword(s):  
Transgenic Mice ◽  
Blood Cell ◽  
Transgenic Mouse ◽  
Red Blood Cell ◽  
Mechanical Stability ◽  
Clinical Status ◽  
Beta Thalassemia ◽  
Membrane Injury ◽  
Protein 4.1 ◽  
Alpha Globin

Abstract In severe human beta-thalassemia, the pathophysiology relates to accumulation of excess alpha-globin chains at the membrane. One hypothesis is that membrane-associated alpha-globin by virtue of it's iron or hemichromes produces oxidation of adjacent membrane proteins. The availability of a mouse model of severe beta-thalassemia, as well as a transgenic (thalassemic-sickle) mouse that expresses 12% of human beta s-chain, has allowed us to study the effect of graded accumulation of alpha-chains at the red blood cell (RBC) membrane on the clinical status of the animal and on the material properties of its RBCs. Proteins from control, beta-thalassemic, and transgenic mouse RBC membranes were analyzed for evidence of oxidation, as measured by thiol- disulfide exchange chromatography, which detects intramolecular sulfhydryl oxidation. Ratios of oxidized globin to protein 7 were calculated and increased amounts were seen in thalassemic mice as compared with control mice and transgenic mice. Furthermore, there were increased amounts of thiol-free protein 4.1 in the thalassemic mice, compared with very small amounts in the control mice and intermediate amounts in the transgenic mice. Membrane mechanical stability as assessed by ektacytometry showed that the thalassemic mouse RBCs were markedly unstable. Transgenic mouse RBCs showed intermediate levels of membrane instability compared with the controls. We propose that this oxidized globin, in conjunction with oxidized protein 4.1, accounts (at least in part) for membrane instability. A 12% increase in beta s- globin chain synthesis (by decreasing excess globin available) confers considerable protection against both oxidative damage and the consequent membrane instability.

scholarly journals The role of membrane skeletal-associated alpha-globin in the pathophysiology of beta-thalassemia

Blood ◽  
1990 ◽  
Vol 75 (6) ◽  
pp. 1333-1336 ◽  
Author(s):  
S Sorensen ◽  
E Rubin ◽  
H Polster ◽  
N Mohandas ◽  
S Schrier
Keyword(s):  
Transgenic Mice ◽  
Blood Cell ◽  
Red Blood Cells ◽  
Red Blood Cell ◽  
Blood Cells ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Cell Deformability ◽  
Red Blood Cell Deformability ◽  
Alpha Globin

Abstract The beta-thalassemic mouse provides a useful model for testing hypotheses about the pathophysiology in human beta-thalassemia. The clinical picture of these mice and their red blood cell deformability characteristics are quite similar to those observed in human beta- thalassemia intermedia. The creation of transgenic mice that express human beta-globin (beta s) has provided an opportunity to study the effect of increasing the non-alpha-globin chain production on the thalassemic phenotype. A small increase in beta-globin production produces transgenic mice that are healthier, have almost normal hemoglobin values, and whose red blood cell deformability is increased. We quantified and characterized the membrane skeletal-associated globin in normal, transgenic thal/sickle, and thalassemic mice and showed that only alpha-globin was associated with the membrane skeleton in the pathologic red blood cells, and that the degree of rigidity as measured in the rheoscope correlated directly and closely with the amount of membrane skeletal-associated globin in these abnormal red blood cells.

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