Fluvastatin protects vascular smooth muscle cells against oxidative stress through the Nrf2-dependent antioxidant pathway

Atherosclerosis. 2010 Dec;213(2):377-84. doi: 10.1016/j.atherosclerosis.2010.07.059. Epub 2010 Aug 19.


Objective: HMG-CoA reductase inhibitors (statins) have pleiotropic actions, including the ability to reduce vascular oxidative stress. Transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important regulator of cellular oxidative stress. This study examined the role of Nrf2 in statin-mediated antioxidant effects in vascular smooth muscle cells.

Methods and results: In cultured human coronary artery smooth muscle cells (hCASMCs), fluvastatin activated the nuclear translocation of Nrf2, as evaluated by Western blotting and immunocytochemical analyses. Nrf2-antioxidant response element (ARE) activity was measured with a luciferase assay after transfection of reporter plasmids containing AREs. Fluvastatin significantly increased the transcriptional activity of the ARE. Electromobility shift assays using an ARE probe detected a complex that was significantly increased in intensity by fluvastatin. Western blotting and luciferase assay revealed fluvastatin activated Nrf2 via the PI3K/Akt pathway. Statins upregulated the Nrf2-related antioxidant genes heme oxygenase-1, NAD(P)H quinone oxidoreductase-1, and glutamate-cysteine ligase modifier subunits. Inhibition of Nrf2 by siRNA reduced statin-induced upregulation of these antioxidant genes. Moreover, Nrf2 siRNA markedly reduced the cytoprotective effects of fluvastatin against H(2)O(2) administration in hCASMCs.

Conclusions: Fluvastatin exerts cytoprotective effects against oxidative stress, inducing antioxidant genes through Nrf2/ARE in hCASMCs. These results suggest that the Nrf2/ARE pathway plays an important role in the regulation of statin-mediated antioxidant effects in vascular smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology*
  • Cells, Cultured
  • Fatty Acids, Monounsaturated / pharmacology*
  • Fluvastatin
  • Glutamate-Cysteine Ligase / metabolism
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Indoles / pharmacology*
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects*
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / physiology*
  • Oxidative Stress / drug effects*
  • Response Elements / physiology


  • Antioxidants
  • Fatty Acids, Monounsaturated
  • Indoles
  • NF-E2-Related Factor 2
  • Fluvastatin
  • Heme Oxygenase-1
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • GCLM protein, human
  • Glutamate-Cysteine Ligase