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Originally published In Press as doi:10.1074/jbc.M104812200 on October 5, 2001

J. Biol. Chem., Vol. 276, Issue 49, 46011-46016, December 7, 2001
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Cell-derived Apolipoprotein E (ApoE) Particles Inhibit Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression in Human Endothelial Cells*

Anita K. StannardDagger §, David R. RiddellDagger , Sandra M. SacreDagger , Aristides D. TagalakisDagger §§, Claus Langer||, Arnold von Eckardstein||**, Paul Cullen||Dagger Dagger , Takis Athanasopoulos§§, George Dickson§§, and James S. OwenDagger ¶¶

From the Dagger  Department of Medicine, Royal Free and University College Medical School, London NW3 2PF, United Kingdom, the || Institut für Arterioskleroseforschung and Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, 48149 Münster, Germany, and the §§ School of Biological Sciences, Royal Holloway University of London, Surrey TW20 0EX, United Kingdom

Sub-endothelial infiltration of monocytes occurs early in atherogenesis and is facilitated by cell adhesion molecules that are up-regulated on activated endothelium. Apolipoprotein E (apoE) helps protect against atherosclerosis, in part, because apoE particles secreted by macrophages have local beneficial effects at lesion sites. Here, we hypothesize that such protection includes anti-inflammatory actions and investigate whether cell-derived apoE can inhibit tumor necrosis factor-alpha -mediated up-regulation of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). Two models were used to mimic endothelial exposure to macrophage-derived apoE. In the first, HUVECs were transiently transfected to secrete apoE; VCAM-1 induction inversely correlated with secretion of apoE into the media (r = -0.76, p < 0.001). In the second, incubation of HUVECs with media from recombinant Chinese hamster ovary (CHO) cells expressing apoE (CHOapoE) also reduced VCAM-1 in a dose-dependent manner (r = -0.70, p < 0.001). Characterization of CHOapoE cell-derived apoE revealed several similarities to apoE particles secreted by human blood monocyte-derived macrophages. The suppression of endothelial activation by apoE most likely occurs via stimulation of endothelial nitric oxide synthase; apoE increased levels of intracellular nitric oxide and its surrogate marker, cyclic guanosine monophosphate, while the nitric oxide synthase inhibitor, ethyl-isothiourea, blocked its effect. We propose that apoE secreted locally at lesion sites by macrophages may be anti-inflammatory by stimulating endothelium to release NO and suppress VCAM-1 expression.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by British Heart Foundation Ph.D. Studentship (FS/95051).

Present address: Neurology Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Ave., Harlow, Essex CM19 5AW, UK

** Supported by the Deutsche Forschungsgemeinschaft (Ec116,3-3).

Dagger Dagger Supported by the Deutsche Forschungsgemeinschaft (Cu 31/4-1).

¶¶ To whom correspondence should be addressed: Dept. of Medicine, Royal Free and Univ. College Medical School, Univ. College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. Tel.: 44-207-4332853; Fax: 44-207-4332852; E-mail: j.owen@rfc.ucl.ac.uk.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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