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Absence of mitochondrial superoxide dismutase results in a murine hemolytic anemia responsive to therapy with a catalytic antioxidant

Academic Article
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Overview

authors

  • Friedman, Jeffrey
  • Rebel, V. I.
  • Derby, R.
  • Bell, K.
  • Huang, T. T.
  • Kuypers, F. A.
  • Epstein, C. J.
  • Burakoff, S. J.

publication date

  • April 2001

journal

  • Journal of Experimental Medicine  Journal

abstract

  • Manganese superoxide dismutase 2 (SOD2) is a critical component of the mitochondrial pathway for detoxification of O2(-), and targeted disruption of this locus leads to embryonic or neonatal lethality in mice. To follow the effects of SOD2 deficiency in cells over a longer time course, we created hematopoietic chimeras in which all blood cells are derived from fetal liver stem cells of Sod2 knockout, heterozygous, or wild-type littermates. Stem cells of each genotype efficiently rescued hematopoiesis and allowed long-term survival of lethally irradiated host animals. Peripheral blood analysis of leukocyte populations revealed no differences in reconstitution kinetics of T cells, B cells, or myeloid cells when comparing Sod2(+/+), Sod2(-/-), and Sod2(+/-) fetal liver recipients. However, animals receiving Sod2(-/-) cells were persistently anemic, with findings suggestive of a hemolytic process. Loss of SOD2 in erythroid progenitor cells results in enhanced protein oxidative damage, altered membrane deformation, and reduced survival of red cells. Treatment of anemic animals with Euk-8, a catalytic antioxidant with both SOD and catalase activities, significantly corrected this oxidative stress-induced condition. Such therapy may prove useful in treatment of human disorders such as sideroblastic anemia, which SOD2 deficiency most closely resembles.

subject areas

  • Anemia, Hemolytic
  • Animals
  • Antioxidants
  • B-Lymphocytes
  • Bone Marrow Cells
  • Cell Transplantation
  • Ethylenediamines
  • Fetal Tissue Transplantation
  • Free Radical Scavengers
  • Genotype
  • Heterozygote
  • Isoenzymes
  • Liver
  • Mice
  • Mice, Knockout
  • Mitochondria
  • Organometallic Compounds
  • Polymerase Chain Reaction
  • Spleen
  • Superoxide Dismutase
  • T-Lymphocytes
  • Thymus Gland
  • Transplantation Chimera
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Research

keywords

  • SOD2
  • antioxidant
  • oxidative stress
  • stem cells
  • transplantation (fetal liver)
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Identity

International Standard Serial Number (ISSN)

  • 0022-1007

Digital Object Identifier (DOI)

  • 10.1084/jem.193.8.925

PubMed ID

  • 11304553
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Additional Document Info

start page

  • 925

end page

  • 934

volume

  • 193

issue

  • 8

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