Syndecan-4 mediates macrophage uptake of group V secretory phospholipase A2-modified low density lipoprotein

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

Internal Medicine, University of Kentucky, Lexington, KY 40536

Corresponding Author: nrwebb1{at}email.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 PI3-kinase inhibitor, significantly reduced internalization of 125I-labeled GV-LDL in J-774 macrophages, consistent with a macropinocytic uptake pathway. Using small interfering RNA (siRNA)-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 to wild type cells. Furthermore, cholesterol ester accumulation induced by GV-LDL was dependent on syndecan-4 expression. Syndecan-4 expression and GV-LDL binding was 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.

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