Journal of Molecular Medicine

, 86:1279

Simvastatin activates Keap1/Nrf2 signaling in rat liver

Authors

  • Ioannis G. Habeos
    • Department of Internal Medicine, School of MedicineUniversity of Patras
  • Panos G. Ziros
    • Department of Internal Medicine, School of MedicineUniversity of Patras
    • Department of Biological ChemistryUniversity of Athens Medical School
  • Dionysios Chartoumpekis
    • Department of Internal Medicine, School of MedicineUniversity of Patras
  • Agathoklis Psyrogiannis
    • Department of Internal Medicine, School of MedicineUniversity of Patras
  • Venetsana Kyriazopoulou
    • Department of Internal Medicine, School of MedicineUniversity of Patras
    • Department of Biological ChemistryUniversity of Athens Medical School
Original Article

DOI: 10.1007/s00109-008-0393-4

Cite this article as:
Habeos, I.G., Ziros, P.G., Chartoumpekis, D. et al. J Mol Med (2008) 86: 1279. doi:10.1007/s00109-008-0393-4

Abstract

Some of the statins’ pleiotropic actions have been attributed to their antioxidant activity. The Nrf2 transcription factor controls the expression of a number of protective genes in response to oxidative stress. In the present study, wistar rats, primary hepatocytes as well as ST2 cells, were employed to explore the potential role of Nrf2 in mediating the reported antioxidant effects of statins. Simvastatin triggered nuclear translocation of Nrf2 in rat liver and in primary rat hepatocytes in a mevalonate-dependent and cholesterol-independent way. In liver, nuclear extracts from simvastatin-treated rats, the DNA-binding activity of Nrf2, was significantly increased and the mRNA of two known targets of Nrf2 (HO-1 and GPX2) was induced. In ST2 cells stably transfected with constructs bearing Nrf2-binding site (antioxidant responsive element), simvastatin enhanced Nrf2-mediated transcriptional activity in a mevalonate-dependent and cholesterol-independent fashion. In conclusion, activation of Keap1/Nrf2 signaling pathway by simvastatin might provide effective protection of the cell from the deleterious effects of oxidative stress.

Keywords

GPX2 HO-1 Hepatocyte Nrf2 Oxidative stress Simvastatin

Abbreviations

ARE

Antioxidant responsive element

DLS

Delipidated serum

DMEM

Dulbecco’s modified Eagle’s medium

DN

Dominant negative

EMSA

Electrophoretic mobility-shift assay

FBS

Fetal bovine serum

GPX

Glutathione peroxidase

HMG-CoA

3-hydroxy-3-methylglutaryl coenzyme A

HO-1

Heme oxygenase 1

NQO1

NAD(P)H:quinone oxidoreductase 1

Nrf2

NF-E2-related factor 2

ROS

Reactive oxygen species

RPA

Ribonuclease protection assay

SREBP-2

Sterol regulatory element-binding protein 2

TRXR

Thioredoxin reductase

Supplementary material

109_2008_393_MOESM1_ESM.pdf (500 kb)
ESM 1 (PDF 499 KB)

Copyright information

© Springer-Verlag 2008