title: Increased endothelial mitogen-activated protein kinase phosphatase-1 expression suppresses proinflammatory activation at sites that are resistant to atherosclerosis.
abstract: 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.
authors: British Heart Foundation Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Mustafa
authors: M
authors: Zakkar
authors: Hera
authors: H
authors: Chaudhury
authors: Gunhild
authors: G
authors: Sandvik
authors: Karine
authors: K
authors: Enesa
authors: Le Anh
authors: le A
authors: Luong
authors: Simon
authors: S
authors: Cuhlmann
authors: Justin C
authors: JC
authors: Mason
authors: Rob
authors: R
authors: Krams
authors: Andrew R
authors: AR
authors: Clark
authors: Dorian O
authors: DO
authors: Haskard
authors: Paul C
authors: PC
authors: Evans
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics; D002478:Cells, Cultured; D002908:Chronic Disease; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis* / Q000235:genetics; D042783:Endothelial Cells / Q000201:enzymology*; D004789:Enzyme Activation / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D033081:Shear Strength; D013314:Stress, Mechanical; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D019010:Vascular Cell Adhesion Molecule-1; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse