title: The Interplay Between Peroxiredoxin-2 and Nuclear Factor-Erythroid 2 Is Important in Limiting Oxidative Mediated Dysfunction in β-Thalassemic Erythropoiesis.
abstract: OBJECTIVE
  β-Thalassemia is a common inherited red cell disorder characterized by ineffective erythropoiesis and severe oxidative stress. Peroxiredoxin-2 (Prx2), a typical 2-cysteine peroxiredoxin, is upregulated during β-thalassemic erythropoiesis, but its contribution to stress erythropoiesis, a common feature of thalassemia, is yet to be fully defined.
  
  
  RESULTS
  Here, we showed that Prx2(-/-) mice displayed reactive oxygen species related abnormalities in erythropoiesis similar to that of Hbb(th3/+) mice associated with activation of redox response transcriptional factor nuclear factor-erythroid 2 (Nrf2). We generated β-thalassemic mice genetically lacking Prx2 (Prx2(-/-)Hbb(th3/+)) and documented a worsened β-thalassemic hematological phenotype with severe ineffective erythropoiesis. To further validate a key role of Prx2 in stress erythropoiesis, we administrated fused recombinant PEP1Prx2 to Hbb(th3/+) mice and documented a decrease in ineffective erythropoiesis. We further show that Prx2 effects are mediated by activation of Nrf2 and upregulation of genes that protect against oxidative damage such as gluthatione S-transferase, heme-oxygenase-1, and NADPH dehydrogenase quinone-1.
  
  
  METHODS
  We propose Prx2 as a key antioxidant system and Nrf2 activation is a cellular adaptive process in response to oxidative stress, resulting in upregulation of antioxidant (antioxidant responsive element) genes required to ensure cell survival.
  
  
  CONCLUSIONS
  Our data shed new light on adaptive mechanisms against oxidative damage through the interplay of Prx2 and Nrf2 during stress erythropoiesis and suggest new therapeutic options to decrease ineffective erythropoiesis by modulation of endogenous antioxidant systems.
authors.affiliation: 1 Department of Medicine, University of Verona-AOUI Verona , Verona, Italy .
authors.forename: Alessandro
authors.initials: A
authors.lastname: Matte
authors.affiliation: 2 CEINGE and Department of Biochemistry, University of Naples , Naples, Italy .
authors.forename: Luigia
authors.initials: L
authors.lastname: De Falco
authors.affiliation: 2 CEINGE and Department of Biochemistry, University of Naples , Naples, Italy .
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
authors.affiliation: 3 New York Blood Center , New York, New York.
authors.forename: Narla
authors.initials: N
authors.lastname: Mohandas
authors.affiliation: 3 New York Blood Center , New York, New York.
authors.forename: Xiuli
authors.initials: X
authors.lastname: An
authors.affiliation: 1 Department of Medicine, University of Verona-AOUI Verona , Verona, Italy .
authors.forename: Angela
authors.initials: A
authors.lastname: Siciliano
authors.affiliation: 4 Inserm , U1165, Paris, France .
authors.forename: Christophe
authors.initials: C
authors.lastname: Leboeuf
authors.affiliation: 4 Inserm , U1165, Paris, France .|5 Université Paris 7 , Denis Diderot, Paris, France .|6 AP-HP, Hôpital Saint-Louis , Paris, France .
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.affiliation: 1 Department of Medicine, University of Verona-AOUI Verona , Verona, Italy .|2 CEINGE and Department of Biochemistry, University of Naples , Naples, Italy .
authors.forename: Mariasole
authors.initials: M
authors.lastname: Bruno
authors.affiliation: 7 Institute of Bioscience and Biotechnology, Hallym University , Chuncheon, Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: 7 Institute of Bioscience and Biotechnology, Hallym University , Chuncheon, Korea.
authors.forename: Dae Won
authors.initials: DW
authors.lastname: Kim
authors.affiliation: 1 Department of Medicine, University of Verona-AOUI Verona , Verona, Italy .
authors.forename: Lucia
authors.initials: L
authors.lastname: De Franceschi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004900:Erythroblasts / Q000378:metabolism; D004909:Erythrocyte Indices / Q000187:drug effects / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D019190:Iron Overload / Q000209:etiology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010641:Phenotype; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D017086:beta-Thalassemia / Q000097:blood* / Q000235:genetics / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D054464:Peroxiredoxins