A transgenic mouse model expressing exclusively human hemoglobin E: Indications of a mild oxidative stress

Qiuying Chen, Mary E. Fabry, Anne C. Rybicki, Sandra M. Suzuka, Tatiana C. Balazs, Zipora Etzion, Kitty de Jong, Edna K. Akoto, Joseph E. Canterino, Dhananjay K. Kaul, Frans A. Kuypers, David Lefer, Eric E. Bouhassira, Rhoda Elison Hirsch

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Hemoglobin (Hb) E (β26 Glu→Lys) is the most common abnormal hemoglobin (Hb) variant in the world. Homozygotes for HbE are mildly thalassemic as a result of the alternate splice mutation and present with a benign clinical picture (microcytic and mildly anemic) with rare clinical symptoms. Given that the human red blood cell (RBC) contains both HbE and excess α-chains along with minor hemoglobins, the consequence of HbE alone on RBC pathophysiology has not been elucidated. This becomes critical for the highly morbid β E-thalassemia disease. We have generated transgenic mice exclusively expressing human HbE (HbEKO) that exhibit the known aberrant splicing of β E globin mRNA, but are essentially non-thalassemic as demonstrated by RBC α/β (human) globin chain synthesis. These mice exhibit hematological characteristics similar to presentations in human EE individuals: microcytic RBC with low MCV and MCH but normal MCHC; target RBC; mild anemia with low Hb, HCT and mildly elevated reticulocyte levels and decreased osmotic fragility, indicating altered RBC surface area to volume ratio. These alterations are correlated with a mild RBC oxidative stress indicated by enhanced membrane lipid peroxidation, elevated zinc protoporphyrin levels, and by small but significant changes in cardiac function. The C57 (background) mouse and full KO mouse models expressing HbE with the presence of HbS or HbA are used as controls. In select cases, the HbA full KO mouse model is compared but found to be limited due to its RBC thalassemic characteristics. Since the HbEKO mouse RBC lacks an abundance of excess α-chains that would approximate a mouse thalassemia (or a human thalassemia), the results indicate that the observed in vivo RBC mild oxidative stress arises, at least in part, from the molecular consequences of the HbE mutation.

Original languageEnglish (US)
Pages (from-to)91-101
Number of pages11
JournalBlood Cells, Molecules, and Diseases
Volume48
Issue number2
DOIs
StatePublished - Feb 15 2012

Fingerprint

Hemoglobin E
Transgenic Mice
Oxidative Stress
Erythrocytes
Thalassemia
Globins
Hemoglobins
Osmotic Fragility
Abnormal Hemoglobins
Mutation
Reticulocytes
Homozygote
Membrane Lipids
Lipid Peroxidation
Anemia

Keywords

  • β-Thalassemia
  • Cardiac function
  • Hemoglobin E
  • Oxidative stress
  • Red blood cells
  • Transgenic mouse model

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Hematology
  • Cell Biology

Cite this

Chen, Q., Fabry, M. E., Rybicki, A. C., Suzuka, S. M., Balazs, T. C., Etzion, Z., ... Hirsch, R. E. (2012). A transgenic mouse model expressing exclusively human hemoglobin E: Indications of a mild oxidative stress. Blood Cells, Molecules, and Diseases, 48(2), 91-101. https://doi.org/10.1016/j.bcmd.2011.12.002

A transgenic mouse model expressing exclusively human hemoglobin E : Indications of a mild oxidative stress. / Chen, Qiuying; Fabry, Mary E.; Rybicki, Anne C.; Suzuka, Sandra M.; Balazs, Tatiana C.; Etzion, Zipora; de Jong, Kitty; Akoto, Edna K.; Canterino, Joseph E.; Kaul, Dhananjay K.; Kuypers, Frans A.; Lefer, David; Bouhassira, Eric E.; Hirsch, Rhoda Elison.

In: Blood Cells, Molecules, and Diseases, Vol. 48, No. 2, 15.02.2012, p. 91-101.

Research output: Contribution to journalArticle

Chen, Q, Fabry, ME, Rybicki, AC, Suzuka, SM, Balazs, TC, Etzion, Z, de Jong, K, Akoto, EK, Canterino, JE, Kaul, DK, Kuypers, FA, Lefer, D, Bouhassira, EE & Hirsch, RE 2012, 'A transgenic mouse model expressing exclusively human hemoglobin E: Indications of a mild oxidative stress', Blood Cells, Molecules, and Diseases, vol. 48, no. 2, pp. 91-101. https://doi.org/10.1016/j.bcmd.2011.12.002
Chen, Qiuying ; Fabry, Mary E. ; Rybicki, Anne C. ; Suzuka, Sandra M. ; Balazs, Tatiana C. ; Etzion, Zipora ; de Jong, Kitty ; Akoto, Edna K. ; Canterino, Joseph E. ; Kaul, Dhananjay K. ; Kuypers, Frans A. ; Lefer, David ; Bouhassira, Eric E. ; Hirsch, Rhoda Elison. / A transgenic mouse model expressing exclusively human hemoglobin E : Indications of a mild oxidative stress. In: Blood Cells, Molecules, and Diseases. 2012 ; Vol. 48, No. 2. pp. 91-101.
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abstract = "Hemoglobin (Hb) E (β26 Glu→Lys) is the most common abnormal hemoglobin (Hb) variant in the world. Homozygotes for HbE are mildly thalassemic as a result of the alternate splice mutation and present with a benign clinical picture (microcytic and mildly anemic) with rare clinical symptoms. Given that the human red blood cell (RBC) contains both HbE and excess α-chains along with minor hemoglobins, the consequence of HbE alone on RBC pathophysiology has not been elucidated. This becomes critical for the highly morbid β E-thalassemia disease. We have generated transgenic mice exclusively expressing human HbE (HbEKO) that exhibit the known aberrant splicing of β E globin mRNA, but are essentially non-thalassemic as demonstrated by RBC α/β (human) globin chain synthesis. These mice exhibit hematological characteristics similar to presentations in human EE individuals: microcytic RBC with low MCV and MCH but normal MCHC; target RBC; mild anemia with low Hb, HCT and mildly elevated reticulocyte levels and decreased osmotic fragility, indicating altered RBC surface area to volume ratio. These alterations are correlated with a mild RBC oxidative stress indicated by enhanced membrane lipid peroxidation, elevated zinc protoporphyrin levels, and by small but significant changes in cardiac function. The C57 (background) mouse and full KO mouse models expressing HbE with the presence of HbS or HbA are used as controls. In select cases, the HbA full KO mouse model is compared but found to be limited due to its RBC thalassemic characteristics. Since the HbEKO mouse RBC lacks an abundance of excess α-chains that would approximate a mouse thalassemia (or a human thalassemia), the results indicate that the observed in vivo RBC mild oxidative stress arises, at least in part, from the molecular consequences of the HbE mutation.",
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AU - Balazs, Tatiana C.

AU - Etzion, Zipora

AU - de Jong, Kitty

AU - Akoto, Edna K.

AU - Canterino, Joseph E.

AU - Kaul, Dhananjay K.

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