Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state

Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1851-7. doi: 10.1161/ATVBAHA.109.193375. Epub 2009 Sep 3.


Objective: Proinflammatory mediators influence atherosclerosis by inducing adhesion molecules (eg, VCAM-1) on endothelial cells (ECs) via signaling intermediaries including p38 MAP kinase. Regions of arteries exposed to high shear stress are protected from inflammation and atherosclerosis, whereas low-shear regions are susceptible. Here we investigated whether the transcription factor Nrf2 regulates EC activation in arteries.

Methods and results: En face staining revealed that Nrf2 was activated in ECs at an atheroprotected region of the murine aorta where it negatively regulated p38-VCAM-1 signaling, but was expressed in an inactive form in ECs at an atherosusceptible site. Treatment with sulforaphane, a dietary antioxidant, activated Nrf2 and suppressed p38-VCAM-1 signaling at the susceptible site in wild-type but not Nrf2(-/-) animals, indicating that it suppresses EC activation via Nrf2. Studies of cultured ECs revealed that Nrf2 inactivates p38 by suppressing an upstream activator MKK3/6 and by enhancing the activity of the negative regulator MKP-1.

Conclusions: Nrf2 prevents ECs at the atheroprotected site from exhibiting a proinflammatory state via the suppression of p38-VCAM-1 signaling. Pharmacological activation of Nrf2 reduces EC activation at atherosusceptible sites and may provide a novel therapeutic strategy to prevent or reduce atherosclerosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arteries / enzymology*
  • Arteries / physiopathology
  • Arteritis / metabolism
  • Arteritis / prevention & control*
  • Cells, Cultured / cytology
  • Cells, Cultured / metabolism
  • Disease Models, Animal
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Enzyme Activation
  • Inflammation Mediators / metabolism
  • Isothiocyanates
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / drug effects
  • NF-E2-Related Factor 2 / metabolism*
  • Phosphorylation / physiology
  • Random Allocation
  • Sensitivity and Specificity
  • Shear Strength
  • Signal Transduction
  • Sulfoxides
  • Thiocyanates / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / drug effects
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Inflammation Mediators
  • Isothiocyanates
  • NF-E2-Related Factor 2
  • Sulfoxides
  • Thiocyanates
  • p38 Mitogen-Activated Protein Kinases
  • sulforaphane