Oxidative stress modulates heme synthesis and induces peroxiredoxin-2 as a novel cytoprotective response in ß-thalassemic erythropoiesis.
Haematologica
; 96(11): 1595-604, 2011 Nov.
Article
em En
| MEDLINE
| ID: mdl-21750082
ABSTRACT
BACKGROUND:
ß-thalassemic syndromes are inherited red cell disorders characterized by severe ineffective erythropoiesis and increased levels of reactive oxygen species whose contribution to ß-thalassemic anemia is only partially understood. DESIGN ANDMETHODS:
We studied erythroid precursors from normal and ß-thalassemic peripheral CD34(+) cells in two-phase liquid culture by proteomic, reverse transcriptase polymerase chain reaction and immunoblot analyses. We measured intracellular reactive oxygen species, heme levels and the activity of δ-aminolevulinate-synthase-2. We exposed normal cells and K562 cells with silenced peroxiredoxin-2 to H(2)O(2) and generated a recombinant peroxiredoxin-2 for kinetic measurements in the presence of H(2)O(2) or hemin.RESULTS:
In ß-thalassemia the increased production of reactive oxygen species was associated with down-regulation of heme oxygenase-1 and biliverdin reductase and up-regulation of peroxiredoxin-2. In agreement with these observations in ß-thalassemic cells we found decreased heme levels related to significantly reduced activity of the first enzyme of the heme pathway, δ-aminolevulinate synthase-2 without differences in its expression. We demonstrated that the activity of recombinant δ-aminolevulinate synthase-2 is inhibited by both reactive oxygen species and hemin as a protective mechanism in ß-thalassemic cells. We then addressed the question of the protective role of peroxiredoxin-2 in erythropoiesis by exposing normal cells to oxidative stress and silencing peroxiredoxin-2 in human erythroleukemia K562 cells. We found that peroxiredoxin-2 expression is up-regulated in response to oxidative stress and required for K562 cells to survive oxidative stress. We then showed that peroxiredoxin-2 binds heme in erythroid precursors with high affinity, suggesting a possible multifunctional cytoprotective role of peroxiredoxin-2 in ß-thalassemia.CONCLUSIONS:
In ß-thalassemic erythroid cells the reduction of δ-aminolevulinate synthase-2 activity and the increased expression of peroxiredoxin-2 might represent two novel stress-response protective systems.
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Base de dados:
MEDLINE
Assunto principal:
Espécies Reativas de Oxigênio
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Talassemia beta
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Estresse Oxidativo
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Eritropoese
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Peroxirredoxinas
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Heme
Limite:
Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article