Oxidative stress modulates heme synthesis and induces peroxiredoxin-2 as a novel cytoprotective response in β-thalassemic erythropoiesis

Lucia de Franceschi, Mariarita Bertoldi, Luigia de Falco, Sara Santos Franco, Luisa Ronzoni, Franco Turrini, Alessandra Colancecco, Clara Camaschella, Maria Domenica Cappellini, Achille Iolascon

Research output: Contribution to journalArticlepeer-review

Abstract

Background β-thalassemic syndromes are inherited red cell disorders characterized by severe ineffective erythropoiesis and increased levels of reactive oxygen species whose contribution to β-thalassemic anemia is only partially understood. Design and Methods We studied erythroid precursors from normal and β-thalassemic peripheral CD34 + cells in twophase 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 2O 2 and generated a recombinant peroxiredoxin-2 for kinetic measurements in the presence of H 2O 2 or hemin. Results In β-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 β-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 β-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 β-thalassemia. Conclusions In b-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.

Original languageEnglish
Pages (from-to)1595-1604
Number of pages10
JournalHaematologica
Volume96
Issue number11
DOIs
Publication statusPublished - Nov 1 2011

Keywords

  • β-thalassemia
  • Heme biosynthesis
  • Oxidative stress
  • Peroxiredoxin-2
  • ROS

ASJC Scopus subject areas

  • Hematology

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