Activation of Nrf2 in Endothelial Cells Protects Arteries From Exhibiting a Proinflammatory State
Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state.
Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1851-7. Epub 2009 Sep 3.
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
British Heart Foundation Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, London, UK.
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.
Note from ISS: Several crucifer sprouts including broccoli sprouts are currently the most potent natural source of sulforaphane known. They often produce 10 to 100 times the amount of sulforaphane as their corresponding mature vegetables.
“Broccoli sprouts have a very high concentration of sulforaphane since this compound originates in the seed and is not made in the plant as it grows. One sprout contains all of the sulforaphane that is present in a full grown broccoli plant.”
“Nutrition and cancer: a review of the evidence for an anti-cancer diet” Nutr J. 2004 Oct 20;3:19, Donaldson MS. Hallelujah Acres Foundation, 13553 Vantage Hwy, Ellensburg, WA 98926, USA.