J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M500241-JLR200 on July 1, 2005

Papers In Press, published online ahead of print September 1, 2005
J. Lipid Res., doi:10.1194/jlr.M500241-JLR200
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Journal of Lipid Research, Vol. 46, 1849-1859, September 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Endostatin binds biglycan and LDL and interferes with LDL retention to the subendothelial matrix during atherosclerosis

Xiaokun Zeng*, Joshua Chen*, Yury I. Miller{dagger}, Kashi Javaherian* and Karen S. Moulton1,*,§

* Vascular Biology Program, Department of Surgery, Children's Hospital, Boston, MA 02115
{dagger} Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093
§ Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115

The online version of this article (available at http://www.jlr.org) contains an additional figure

Published, JLR Papers in Press, July 1, 2005. DOI 10.1194/jlr.M500241-JLR200

1 To whom correspondence should be addressed. e-mail: karen.moulton{at}childrens.harvard.edu

Retention of lipoproteins to proteoglycans in the subendothelial matrix (SEM) is an early event in atherosclerosis. We recently reported that collagen XVIII and its proteolytically released fragment endostatin (ES) are differentially depleted in blood vessels affected by atherosclerosis. Loss of collagen XVIII/ES in atherosclerosis-prone mice enhanced plaque neovascularization and increased the vascular permeability to lipids by distinct mechanisms. Impaired endothelial barrier function increased the influx of lipoproteins across the endothelium; however, we hypothesized that enhanced retention might be a second mechanism leading to the increased lipid content in atheromas lacking collagen XVIII. We now demonstrate a novel property of ES that binds both the matrix proteoglycan biglycan and LDL and interferes with LDL retention to biglycan and to SEM. A peptide encompassing the {alpha} coil in the ES crystal structure mediates the major blocking effect of ES on LDL retention. ES inhibits the macrophage uptake of biglycan-associated LDL indirectly by interfering with LDL retention to biglycan, but it has no direct effect on the macrophage uptake of native or modified lipoproteins.

Thus, loss of ES in advanced atheromas enhances lipoprotein retention in SEM. Our data reveal a third protective role of this vascular basement membrane component during atherosclerosis.

Abbreviations: Bmax, maximum density of binding sites in matrix; ES, endostatin; GAG, glycosaminoglycan; HBS, HEPES-buffered saline; HUVEC, human umbilical vein endothelial cells; Kd, dissociation constant; OxLDL, oxidized low density lipoprotein; SEM, subendothelial matrix

Supplementary key words low density lipoprotein • extracellular matrix • vascular basement membrane • proteoglycans • collagen XVIII


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