Journal of Molecular Medicine

, Volume 89, Issue 10, pp 1027–1035 | Cite as

Nrf2-dependent gene expression is affected by the proatherogenic apoE4 genotype—studies in targeted gene replacement mice

  • Anne-Christin Graeser
  • Christine Boesch-Saadatmandi
  • Jana Lippmann
  • Anika E. Wagner
  • Patricia Huebbe
  • Niels Storm
  • Wolfgang Höppner
  • Ingrid Wiswedel
  • Andreas Gardemann
  • Anne M. Minihane
  • Frank Döring
  • Gerald Rimbach
Original Article

Abstract

An apoE4 genotype is an important risk factor for cardiovascular and other chronic diseases. The higher cardiovascular disease risk of apoE4 carriers as compared to the apoE3 genotype has been mainly attributed to the differences in blood lipids between the two genotype subgroups. Recently, a potential protective role of the transcription factor Nrf2 in cardiovascular disease prevention has been suggested. In this study, we show that Nrf2-dependent gene expression is affected by the apoE genotype. ApoE4 vs. apoE3 mice exhibited lower hepatic Nrf2 nuclear protein levels. Furthermore, mRNA and protein levels of Nrf2 target genes including glutathione-S-transferase, heme oxygenase-1 and NAD(P)H dehydrogenase, quinone 1 were significantly lower in apoE4 as compared to apoE3 mice. Lower hepatic mRNA levels of phase II enzymes, as observed in apoE4 vs. apoE3 mice, were accompanied by higher mRNA levels of phase I enzymes including Cyp26a1 and Cyp3a16. Furthermore, miRNA-144, miRNA-125b, and miRNA-29a involved in Nrf2 signaling, inflammation, and regulation of phase I enzyme gene expression were affected by the apoE genotype. We provide first evidence that Nrf2 is differentially regulated in response to the apoE genotype.

Keywords

Cardiovascular disease Nrf2 ApoE Glutathione-S-transferase Heme oxygenase-1 MicroRNA Mice 

Notes

Acknowledgments

We thank the German Ministry of Education and Science (BMBF 0313856A, BMBF 0315397C) and the DFG Cluster of Excellence “Inflammation at Interfaces” for financial support. A.C.G. is supported by a grant from H. W. Schaumann foundation.

Disclosure statement

The authors declare that they have no competing interests.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Anne-Christin Graeser
    • 1
  • Christine Boesch-Saadatmandi
    • 1
  • Jana Lippmann
    • 1
  • Anika E. Wagner
    • 1
  • Patricia Huebbe
    • 1
  • Niels Storm
    • 2
  • Wolfgang Höppner
    • 2
  • Ingrid Wiswedel
    • 3
  • Andreas Gardemann
    • 3
  • Anne M. Minihane
    • 4
  • Frank Döring
    • 5
  • Gerald Rimbach
    • 1
  1. 1.Institute of Human Nutrition and Food Science, Department of Food ScienceChristian-Albrechts-University KielKielGermany
  2. 2.Bioglobe GmbHHamburgGermany
  3. 3.Department of Pathological Biochemistry, Medical FacultyOtto-von-Guericke-UniversityMagdeburgGermany
  4. 4.School of MedicineUniversity of East AngliaNorwichUK
  5. 5.Department of Molecular PreventionInstitute of Human Nutrition and Food Science, Christian-Albrechts-University KielKielGermany

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