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


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.
Zakkar
Mustafa
M
British Heart Foundation Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, London, UK.
Van der Heiden
Kim
K
Luong
Le Anh
le A
Chaudhury
Hera
H
Cuhlmann
Simon
S
Hamdulay
Shahir S
SS
Krams
Rob
R
Edirisinghe
Indika
I
Rahman
Irfan
I
Carlsen
Harald
H
Haskard
Dorian O
DO
Mason
Justin C
JC
Evans
Paul C
PC
D000818:Animals; D001158:Arteries / Q000201:enzymology* / Q000503:physiopathology; D001167:Arteritis / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation; D018836:Inflammation Mediators / Q000378:metabolism; D017879:Isothiocyanates; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011897:Random Allocation; D012680:Sensitivity and Specificity; D033081:Shear Strength; D015398:Signal Transduction; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D018836:Inflammation Mediators; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D013454:Sulfoxides; D013861:Thiocyanates; D048051:p38 Mitogen-Activated Protein Kinases; C016766:sulforaphane