RRC ID 6058
Author Zakkar M, Van der Heiden K, Luong le A, Chaudhury H, Cuhlmann S, Hamdulay SS, Krams R, Edirisinghe I, Rahman I, Carlsen H, Haskard DO, Mason JC, Evans PC.
Title Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state.
Journal Arterioscler Thromb Vasc Biol
Abstract 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.
Volume 29(11)
Pages 1851-7
Published 2009-11-1
DOI 10.1161/ATVBAHA.109.193375
PII ATVBAHA.109.193375
PMID 19729611
MeSH 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*
IF 6.604
Times Cited 160
Mice RBRC01390