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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1851.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Activation of Nrf2 in Endothelial Cells Protects Arteries From Exhibiting a Proinflammatory State

Mustafa Zakkar; Kim Van der Heiden; Le Anh Luong; Hera Chaudhury; Simon Cuhlmann; Shahir S. Hamdulay; Rob Krams; Indika Edirisinghe; Irfan Rahman; Harald Carlsen; Dorian O. Haskard; Justin C. Mason; Paul C. Evans

From the British Heart Foundation Cardiovascular Sciences Unit (M.Z., K.V.d.H., L.A.L., H.C., S.C., S.S.H., D.O.H., J.C.M., P.C.E.), National Heart and Lung Institute, Imperial College London, UK; the Department of Bioengineering (S.C., R.K.), Imperial College London, UK; University of Rochester Medical Center (I.E., I.R.), Rochester, NY; and the Department of Nutrition (H.C.), University of Oslo, Norway.

Correspondence to Dr Paul C. Evans, Senior Lecturer, British Heart Foundation Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, UK. E-mail paul.evans{at}imperial.ac.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.

Atherosclerosis is a focal disease. Here we demonstrate that the transcription factor Nrf2 suppresses endothelial activation at atheroprotected sites by inhibiting p38 phosphorylation. Moreover, pharmacological activation of Nrf2 reduced endothelial activation at an atherosusceptible site and may provide a novel therapeutic strategy to prevent or reduce atherosclerosis.

Key Words: Nrf2 • arterial endothelium • shear stress • sulforaphane • proinflammatory activation • p38 • MKK3/6 • MKP-1