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

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 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 H2O2 and generated a recombinant peroxiredoxin-2 for kinetic measurements in the presence of H2O2 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 β-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.

• Publication year

  2011

• Venue

  Haematologica

• Publication date

  2011-11-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3324/haematol.2011.043612PMID 21750082PMCID PMC3208676
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The thalassemia syndromes.

  2016cited by this paper
• The coordinated increased expression of biliverdin reductase and heme oxygenase‐2 promotes cardiomyocyte survival: a reductase‐based peptide counters β‐adrenergic receptor ligand‐mediated cardiac dysfunction

  2011cited by this paper
• Enhanced Translation of Heme Oxygenase-2 Preserves Human Endothelial Cell Viability during Hypoxia*

  2010cited by this paper
• Beta-thalassemia

  2010cited by this paper
• Peroxiredoxin-2 expression is increased in beta-thalassemic mouse red cells but is displaced from the membrane as a marker of oxidative stress.

  2010cited by this paper
• Deoxygenation affects tyrosine phosphoproteome of red cell membrane from patients with sickle cell disease.

  2010cited by this paper
• The 2-Cys Peroxiredoxin Alkyl Hydroperoxide Reductase C Binds Heme and Participates in Its Intracellular Availability in Streptococcus agalactiae*

  2010cited by this paper
• Chaperoning erythropoiesis.

  2009cited by this paper
• Disorders of hemoglobin: Genetics, pathophysiology, and clinical management, second edition

  2009cited by this paper
• HSP27: mechanisms of cellular protection against neuronal injury.

  2009cited by this paper
• Erythroid differentiation and maturation from peripheral CD34+ cells in liquid culture: cellular and molecular characterization.

  2008cited by this paper
• PTPϵ has a critical role in signaling transduction pathways and phosphoprotein network topology in red cells

  2008cited by this paper
• Proteomic analysis of erythroid differentiation induced by hexamethylene bisacetamide in murine erythroleukemia cells.

  2007cited by this paper
• An erythroid chaperone that facilitates folding of α-globin subunits for hemoglobin synthesis

  2007cited by this paper
• An erythroid chaperone that facilitates folding of alpha-globin subunits for hemoglobin synthesis.

  2007cited by this paper
• K-CL co-transport plays an important role in normal and β thalassemic erythropoiesis

  2007cited by this paper
• Peroxiredoxin 2 functions as a noncatalytic scavenger of low-level hydrogen peroxide in the erythrocyte.

  2007cited by this paper
• Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias.

  2007cited by this paper
• Heme as a magnificent molecule with multiple missions: heme determines its own fate and governs cellular homeostasis.

  2007cited by this paper
• Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis.

  2006cited by this paper
• Oxidation state governs structural transitions in peroxiredoxin II that correlate with cell cycle arrest and recovery

  2006cited by this paper
• Quantitative proteomics reveals posttranslational control as a regulatory factor in primary hematopoietic stem cells.

  2006cited by this paper
• α‐Haemoglobin stabilising protein is a quantitative trait gene that modifies the phenotype of β‐thalassaemia

  2006cited by this paper
• Alpha-haemoglobin stabilising protein is a quantitative trait gene that modifies the phenotype of beta-thalassaemia.

  2006cited by this paper
• The single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction: twenty-something years on

  2006cited by this paper
• Lyn kinase promotes erythroblast expansion and late-stage development.

  2006cited by this paper
• Molecular control of vertebrate iron homeostasis by iron regulatory proteins.

  2006cited by this paper
• Identification of heme binding protein complexes in murine erythroleukemic cells: Study by a novel two‐dimensional native separation – liquid chromatography and electrophoresis

  2005cited by this paper
• Heme-regulated eIF2α kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and β-thalassemia

  2005cited by this paper
• A proteomic analysis of murine bone marrow and its response to ionizing radiation

  2005cited by this paper
• MEDICAL PROGRESS : β-thalassemia

  2005cited by this paper
• Beta-thalassemia.

  2005cited by this paper
• Heme binding by the N-terminal fragment 1-44 of human growth hormone.

  2005cited by this paper
• Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia.

  2005cited by this paper
• Thalassemia syndromes.

  2004cited by this paper
• Flow cytometric measurement of reactive oxygen species production by normal and thalassaemic red blood cells

  2003cited by this paper
• Biliverdin reductase: A major physiologic cytoprotectant

  2002cited by this paper
• Proteomics Analysis of Cellular Response to Oxidative Stress

  2002cited by this paper
• Regulation of delta-aminolevulinate synthase activity during the development of oxidative stress.

  1999cited by this paper
• Regulation of delta-aminolevulinate synthase activity during the development of oxidative stress.

  1999cited by this paper
• Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload

  1999cited by this paper
• Regulation of erythroid 5-aminolevulinate synthase expression during erythropoiesis.

  1999cited by this paper
• Techniques for studying stimulation of fetal hemoglobin production in human erythroid cultures.

  1998cited by this paper
• Severe energy impairment consequent to inactivation of mitochondrial ATP synthase as an early event in cell death: a mechanism for the selective sensitivity to H2O2 of differentiating erythroleukemia cells.

  1998influential reference
• Characterization of a Mammalian Peroxiredoxin That Contains One Conserved Cysteine*

  1998cited by this paper
• Can ferritin provide iron for hemoglobin synthesis?

  1997cited by this paper
• Thioredoxin Peroxidase Is a Novel Inhibitor of Apoptosis with a Mechanism Distinct from That of Bcl-2*

  1997cited by this paper
• Effect of active oxygen radicals on protein and carbohydrate moieties of recombinant human erythropoietin.

  1997cited by this paper
• A continuous spectrophotometric assay for 5-aminolevulinate synthase that utilizes substrate cycling.

  1995cited by this paper
• Early events in erythroid differentiation: accumulation of the acidic peroxidoxin (PRP/TSA/NKEF-B).

  1995cited by this paper
• Purification, characterization, and cloning of a heme-binding protein (23 kDa) in rat liver cytosol.

  1995cited by this paper
• Oxidative damage and erythrocyte membrane transport abnormalities in thalassemias.

  1994cited by this paper
• Estimation of plasma and urinary hemoglobin by a rate spectrophotometric method.

  1993cited by this paper
• Regulation by heme of mitochondrial protein transport through a conserved amino acid motif.

  1993cited by this paper
• Viability measurements in mammalian cell systems.

  1989cited by this paper
• Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

  1987cited by this paper

• ALAS2 Prevents Neonatal Necrotizing Enterocolitis by Improving Ferroptosis in Intestinal Epithelial Cells Through Inhibition of Oxidative Stress

  2026cites this paper
• Application of nimodipine combined with statins in the treatment of subarachnoid haemorrhage.

  2025cites this paper
• Oxidative stress markers and tissue iron overload after 12-months vitamin E supplementation for children with transfusion-dependent β-thalassemia on different iron chelators: A randomized placebo-controlled trial.

  2025cites this paper
• Protein biomarkers for bipolar II disorder are correlated with affective cognitive performance

  2025cites this paper
• Peroxiredoxins as novel indicators in multiple myeloma associated with ferroptosis and immune infiltration

  2025cites this paper
• RUNX2 isoform II protects cancer cells from ferroptosis and apoptosis by promoting PRDX2 expression in oral squamous cell carcinoma

  2025cites this paper
• Mitapivat metabolically reprograms human β-thalassemic erythroblasts, increasing their responsiveness to oxidation

  2025cites this paper
• PRDX2 induces tumor immune evasion by modulating the HDAC3-Galectin-9 axis in lung adenocarcinoma cells

  2025cites this paper
• Modulation of Antioxidant Enzyme Expression of In Vitro Culture-Derived Reticulocytes

  2024cites this paper
• CSF Markers of Oxidative Stress Are Associated with Brain Atrophy and Iron Accumulation in a 2-Year Longitudinal Cohort of Early MS

  2023cites this paper
• The categorizations of vasculogenic mimicry in clear cell renal cell carcinoma unveil inherent connections with clinical and immune features

  2023cites this paper
• Peroxiredoxins in erythrocytes: far beyond the antioxidant role

  2023cites this paper
• across human immune cells

  2023cites this paper
• Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells

  2023cites this paper
• Single-cell multi-omics reveals dynamics of purifying selection of pathogenic mitochondrial DNA across human immune cells

  2022cites this paper
• Transcriptomic analysis reveals genetic factors regulating early steroid-induced osteonecrosis of the femoral head

  2022cites this paper
• Interferon-alpha2 treatment of patients with polycythemia vera and related neoplasms favorably impacts deregulation of oxidative stress genes and antioxidative defense mechanisms

  2022cites this paper
• Epigenome-wide association study of short-term temperature fluctuations based on within-sibship analyses in Australian females.

  2022cites this paper
• Beta‐thalassemia and the advent of new interventions beyond transfusion and iron chelation

  2022cites this paper
• Erythrocytes as a preferential target of oxidative stress in blood

  2021cites this paper
• Antioxidant Gene Signature Impacts the Immune Infiltration and Predicts the Prognosis of Kidney Renal Clear Cell Carcinoma

  2021cites this paper
• Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β–Thalassemia

  2021cites this paper
• Identification of potential plasma protein biomarkers for bipolar II disorder: a preliminary/exploratory study

  2021cites this paper
• Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

  2021cites this paper
• The Hsp70 chaperone system: distinct roles in erythrocyte formation and maintenance

  2021cites this paper
• The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model.

  2021cites this paper
• Tyrosine Phosphorylation Modulates Peroxiredoxin-2 Activity in Normal and Diseased Red Cells

  2021cites this paper
• Eritrositlerde Oksidatif Stres Oluşumunda Rol Oynayan Özgül Mekanizmalar ve Koruyucu Antioksidan Sistemler

  2020cites this paper
• Specific Mechanisms and Protective Antioxidant Systems Playing Role in Occurring Oxidative Stress in Erythrocytes

  2020cites this paper
• Peroxiredoxin 2 is highly expressed in human oral squamous cell carcinoma cells and is upregulated by human papillomavirus oncoproteins and arecoline, promoting proliferation

  2020cites this paper
• Effects of Selenium Deficiency in the Environment on Antioxidant Systems of Wumen Semi-Fine Wool Sheep

  2020cites this paper
• Expression of South East Asian Ovalocytic Band 3 Disrupts Erythroblast Cytokinesis and Reticulocyte Maturation

  2020cites this paper
• Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders

  2020cites this paper
• Molecular connections between circadian rhythm and genome maintenance pathways.

  2020cites this paper
• Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of beta-thalassemia.

  2019influential citation
• PRDX2 protects against oxidative stress induced by H. pylori and promotes resistance to cisplatin in gastric cancer

  2019cites this paper
• Oxidation and erythropoiesis

  2019cites this paper
• Oxidative Stress and Iron Overload in β-Thalassemia: An Overview

  2019cites this paper
• The intricate role of selenium and selenoproteins in erythropoiesis

  2018cites this paper
• Pharmacoproteomics Profiling of Plasma From β‐Thalassemia Patients in Response to Hydroxyurea Treatment

  2018cites this paper
• Prospective Discrimination of Controllers From Progressors Early After Low-Dose Mycobacterium tuberculosis Infection of Cynomolgus Macaques using Blood RNA Signatures

  2018cites this paper
• Global analysis of erythroid cells redox status reveals the involvement of Prdx1 and Prdx2 in the severity of beta thalassemia

  2018cites this paper
• Oxidative Stress in β-Thalassemia

  2018cites this paper
• Peroxiredoxin-2: A Novel Regulator of Iron Homeostasis in Ineffective Erythropoiesis

  2018cites this paper
• Homeostasis of Oxidative-Related Metabolism in Human Erythrocyte: An Overview of the Hemoglobin S Presence Implications

  2018cites this paper
• TO MONITOR TREATMENT OF A LARGE COHORT OF PATIENTS WITH β-THALASSAEMIA MAJOR, INTERMEDIA & SICKLE CELL ANAEMIA IN ORDER TO ESTABLISH THE RESPONSE TO TRANS-RESVERATROL AND THE ASSOCIATED ELEMENTS.

  2017cites this paper
• Nrf-2-driven long noncoding RNA ODRUL contributes to modulating silver nanoparticle-induced effects on erythroid cells.

  2017cites this paper
• Pathophysiology and treatment of patients with beta-thalassemia – an update

  2017cites this paper
• A S uccessful Generation of Erythroid Precursors from HbE / Beta Thalassemia Patients using Peripheral Blood Mononuclear Cells

  2017cites this paper
• Peroxiredoxin 2 Plays a Pivotal Role Against Oxidation in the Early Phase of Pulmonary Artery Hypertension

  2017cites this paper
• Noncoding RNAs as Critical Players in Regulatory Accuracy, Redox Signaling, and Immune Cell Functions

  2017cites this paper
• Overexpression of stress-related genes in Cuscuta campestris in response to host defense reactions

  2017cites this paper
• Correlation of BACH1 and Hemoglobin E/Beta-Thalassemia Globin Expression

  2016cites this paper
• Analysis of protein profiling studies of β‐thalassemia/Hb E disease

  2016cites this paper
• Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization

  2016cites this paper
• Protease inhibitors‐based therapy induces acquired spherocytic‐like anaemia and ineffective erythropoiesis in chronic hepatitis C virus patients

  2016cites this paper
• 2017 Clinical trials update in new treatments of β‐thalassemia

  2016cites this paper
• The Interplay Between Peroxiredoxin-2 and Nuclear Factor-Erythroid 2 Is Important in Limiting Oxidative Mediated Dysfunction in β-Thalassemic Erythropoiesis

  2015cites this paper
• Modelling and analysis of peroxiredoxin kinetics for systems biology applications.

  2015cites this paper
• Nuclear redox imbalance affects circadian oscillation in HaCaT keratinocytes.

  2015cites this paper
• Review: Beta-thalassemia and molecular chaperones.

  2015cites this paper
• Human Peroxiredoxins 1 and 2 and Their Interacting Protein Partners; Through Structure Toward Functions of Biological Complexes.

  2015cites this paper
• Sampangine (a Copyrine Alkaloid) Exerts Biological Activities through Cellular Redox Cycling of Its Quinone and Semiquinone Intermediates.

  2015cites this paper
• The interplay between peroxiredoxin-2 and Nrf2 is important in limiting oxidative mediated dysfunction in b-thalassemic erythropoiesis

  2015cites this paper
• Oxidative stress in β-thalassaemia and sickle cell disease

  2015cites this paper
• Thalassemia major patients using iron chelators showed a reduced plasma thioredoxin level and reduced thioredoxin reductase activity, despite elevated oxidative stress

  2015cites this paper
• Resveratrol accelerates erythroid maturation by activation of FoxO3 and ameliorates anemia in beta-thalassemic mice

  2014cites this paper
• Improved Hematopoietic Differentiation Efficiency of Gene-Corrected Beta-Thalassemia Induced Pluripotent Stem Cells by CRISPR/Cas9 System

  2014cites this paper
• The novel role of peroxiredoxin-2 in red cell membrane protein homeostasis and senescence.

  2014cites this paper
• 1 Improved hematopoietic differentiation efficiency of gene-corrected beta-thalassemia induced pluripotent stem cells by CRISPR / Cas 9 system Running title : Differentiation of gene-corrected β-Thal iPS

  2014cites this paper
• Antioxidants as Complementary Medication in Thalassemia

  2014cites this paper
• Kolaviron and vitamin E ameliorate hematotoxicity and oxidative stress in brains of prepubertal rats treated with an anticonvulsant phenytoin

  2014cites this paper
• α -Hemoglobin Stabilizing Protein (AHSP) Perturbs the Proximal Heme Pocket of Oxy- α -Hemoglobin and Weakens the Iron-Oxygen Bond*

  2013cites this paper
• ATP-Binding Cassette B10 Regulates Early Steps of Heme Synthesis

  2013cites this paper
• α-Hemoglobin-stabilizing Protein (AHSP) Perturbs the Proximal Heme Pocket of Oxy-α-hemoglobin and Weakens the Iron-Oxygen Bond*

  2013cites this paper
• Hemopexin Therapy Improves Cardiovascular Function by Preventing Heme-Induced Endothelial Toxicity in Mouse Models of Hemolytic Diseases

  2013cites this paper
• Oxidative Stress and β-Thalassemic Erythroid Cells behind the Molecular Defect

  2013cites this paper
• Rôle de la chaperonne HSP 70 dans l'éythropoïèse inefficace des béta-thalassémies majeures

  2013cites this paper
• Membrane association of peroxiredoxin-2 in red cells is mediated by the N-terminal cytoplasmic domain of band 3.

  2013cites this paper
• Erythroid cells generated in the absence of specific β1-integrin heterodimers accumulate reactive oxygen species at homeostasis and are unable to mount effective antioxidant defenses

  2013cites this paper
• Ineffective Erythropoiesis in β-Thalassemia

  2013cites this paper
• Pharmacological inhibition of calpain‐1 prevents red cell dehydration and reduces Gardos channel activity in a mouse model of sickle cell disease

  2013cites this paper
• ORIGINAL RESEARCH ARTICLE Glycolytic Enzyme Profile in Beta-Thalassemia Major: Coordinated Alterations in Hexokinase, Pyruvate Kinase, and Phosphofructokinase with Implications for Therapeutic Targeting

  year unknowncites this paper