This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 103/7/726    most recent CIRCRESAHA.108.183913v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zakkar, M. Articles by Evans, P. C. Search for Related Content PubMed PubMed Citation Articles by Zakkar, M. Articles by Evans, P. C. Related Collections Pathophysiology Cell signalling/signal transduction Endothelium/vascular type/nitric oxide

(Circulation Research. 2008;103:726.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Increased Endothelial Mitogen-Activated Protein Kinase Phosphatase-1 Expression Suppresses Proinflammatory Activation at Sites That Are Resistant to Atherosclerosis

Mustafa Zakkar, Hera Chaudhury, Gunhild Sandvik, Karine Enesa, Le Anh Luong, Simon Cuhlmann, Justin C. Mason, Rob Krams, Andrew R. Clark, Dorian O. Haskard, Paul C. Evans

From the British Heart Foundation Cardiovascular Sciences Unit (M.Z., H.C., G.S., K.E., L.A.L., S.C., J.C.M., D.O.H., P.C.E.), National Heart and Lung Institute; and Department of Bioengineering (R.K.) and the Kennedy Institute of Rheumatology Division (A.R.C.), Imperial College, London, United Kingdom.

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

Atherosclerosis is a chronic inflammatory disease of arteries. It is triggered by proinflammatory mediators which induce adhesion molecules (eg, vascular cell adhesion molecule [VCAM]-1) in endothelial cells (ECs) by activating p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases by phosphorylation. Blood flow influences atherosclerosis by exerting shear stress (mechanical drag) on the inner surface of arteries, a force that alters endothelial physiology. Regions of the arterial tree exposed to high shear are protected from endothelial activation, inflammation, and atherosclerosis, whereas regions exposed to low or oscillatory shear are susceptible. We examined whether MAP kinase phosphatase (MKP)-1, a negative regulator of p38 and JNK, mediates the antiinflammatory effects of shear stress. We observed that expression of MKP-1 in cultured ECs was elevated by shear stress, whereas the expression of VCAM-1 was reduced. MKP-1 induction was shown to be necessary for the antiinflammatory effects of shear stress because gene silencing of MKP-1 restored VCAM-1 expression in sheared ECs. Immunostaining revealed that MKP-1 is preferentially expressed by ECs in a high-shear, protected region of the mouse aorta and is necessary for suppression of EC activation at this site, because p38 activation and VCAM-1 expression was enhanced by genetic deletion of MKP-1. We conclude that MKP-1 induction is required for the antiinflammatory effects of shear stress. Thus, our findings reveal a novel molecular mechanism contributing to the spatial distribution of vascular inflammation and atherosclerosis.

Key Words: atherosclerosis • endothelial cells • shear stress • MAP kinases • MAP kinase phosphatase-1

This article has been cited by other articles:

				M. Zakkar, K. Van der Heiden, L. A. Luong, H. Chaudhury, S. Cuhlmann, S. S. Hamdulay, R. Krams, I. Edirisinghe, I. Rahman, H. Carlsen, et al. Activation of Nrf2 in Endothelial Cells Protects Arteries From Exhibiting a Proinflammatory State Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1851 - 1857. [Abstract] [Full Text] [PDF]

				L. K. Curtiss and P. S. Tobias Emerging role of Toll-like receptors in atherosclerosis J. Lipid Res., April 1, 2009; 50(Supplement): S340 - S345. [Abstract] [Full Text] [PDF]