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Journal of Lipid Research, Vol. 50, 641-650, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Syndecan-4 mediates macrophage uptake of group V secretory phospholipase A₂-modified LDL^*

Boris B. Boyanovsky^*, Preetha Shridas, Michael Simons^**, Deneys R. van der Westhuyzen^*,, and Nancy R. Webb^1,*,,

^* Department of Internal Medicine, Endocrinology Division, University of Kentucky Medical Center, Lexington, KY 40536
Cardiovascular Research Center, University of Kentucky Medical Center, Lexington, KY 40536
Graduate Center for Nutritional Sciences, University of Kentucky Medical Center, Lexington, KY 40536
^** Yale University School of Medicine, New Haven, CT 06520

^* This work was funded by National Institutes of Health Grant RO1HL-071098 to N.R.W. The authors thank Kathy Forrest and William Bailey for excellent technical assistance.

Published, JLR Papers in Press, December 3, 2008.

¹ To whom correspondence should be addressed. e-mail: nrwebb1{at}uky.edu

We previously reported that LDL modified by group V secretory phospholipase A₂ (GV-LDL) promotes macrophage foam cell formation through a mechanism independent of scavenger receptors SR-A and CD36, and dependent on cellular proteoglycans. This study investigates the role of syndecans, a family of cell surface proteoglycans known to mediate endocytosis through macropinocytosis, in macrophage uptake of GV-LDL. LY 294002, a phosphatidylinositol 3-kinase inhibitor, significantly reduced internalization of ¹²⁵I-labeled GV-LDL in J-774 macrophages, consistent with a macropinocytic uptake pathway. Using small, interfering RNA-directed gene silencing, we demonstrated a direct relationship between ¹²⁵I-labeled GV-LDL binding and the level of syndecan-3 and syndecan-4 expression in J-774 cells. However, ¹²⁵I-labeled GV-LDL uptake was significantly reduced only when syndecan-4 expression was suppressed. Peritoneal macrophages from syndecan-4-deficient mice exhibited markedly reduced uptake of fluorescently labeled GV-LDL compared with wild-type cells. Furthermore, cholesteryl ester accumulation induced by GV-LDL was dependent on syndecan-4 expression. Syndecan-4 expression and GV-LDL binding were significantly increased in J-774 cells treated with lipopolysaccharide, suggesting that GV-LDL uptake via this pathway may be enhanced during inflammation. Taken together, our data point to a novel role for syndecan-4 in mediating the uptake of GV-LDL, a process implicated in atherosclerotic lesion progression.

Supplementary key words atherosclerosis • foam cells • macropinocytosis • proteoglycan • lipoprotein modification

Abbreviations: apoB-100, apolipoprotein B-100; CE, cholesteryl ester; ECM, extracellular matrix; GAG, glucosaminoglycan; GV, group V; HSPG, heparan sulfate proteoglycan; LPS, lipopolysaccharide; MPM, mouse peritoneal macrophage; ox-LDL, oxidized LDL; PI, phosphatidylinositol; sPLA₂, secretory phospholipase A₂

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