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

Abstract

We previously reported that LDL modified by group V secretory phospholipase A 2 (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 125 I-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 125 I-labeled GV-LDL binding and the level of syndecan-3 and syndecan-4 expression in J-774 cells. However, 125 I-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.-Boyanovsky, B. B., P. Shridas, M. Simons, D. R. van der Westhuyzen, and N. R. Webb. Syndecan-4 mediates macrophage uptake of group V secretory phospholipase A 2 -modified LDL. J. Lipid Res. 2009. 50: 641-650.

Eicosapentaenoic Acid and Docosahexaenoic Acid Regulate Modified LDL Uptake and Macropinocytosis in Human Macrophages

“…3) may also explain how AcLDL uptake, and OxLDL uptake in the case of DHA, is reduced independent of changes in the expression of scavenger receptors. Indeed, our data implicate modified LDL as a potential ligand for Syndecan-4 mediated endocytosis since GV-LDL has been identified as a target ligand [40].…”

“…In order to further explain these reductions in LY uptake, we next analyzed whether EPA and DHA altered Syndecan-4 expression in these cells. Syndecan-4 is a cell surface heparan sulfate proteoglycan that can be endocytosed through the macropinocytic pathway [38] and can mediate uptake of LPL-enriched LDL [39] and group V secretory phospholipase A 2 -modified LDL (GV-LDL) [40]. We found that EPA and DHA produced a statistically significant decrease in Syndecan-4 mRNA expression in THP-1 macrophages (Fig.…”

Calcium-Independent Phospholipase A2β-Akt Signaling Is Involved in Lipopolysaccharide-Induced NADPH Oxidase 1 Expression and Foam Cell Formation

“…Recently, it was reported that group III sPLA 2 modifies LDL, facilitating the conversion from macrophage to foam cells (44). Very recently, it was reported that syndecan-4 controls uptake of modified LDL by group V sPLA 2 (45). The overall mechanism of sPLA 2 in foam cell formation is suggested to comprise modification of lipoproteins (46,47) or sPLA 2 -hydrolyzed lysophosphatidylcholine (LPC) (48).…”

Acidification of the intimal fluid: the perfect storm for atherogenesis

“…Extracellular acidosis enhances the uptake of native and modifi ed LDL particles by macrophages through increases in the levels of cell surface proteoglycans, and of LDL-proteoglycan binding ( 69,125 ). These proteoglycans are most likely heparan-sulfate-rich proteoglycans of the syndecan family ( 126,127 ). Extracellular acidosis may also accelerate foam cell formation by enhancing lipoprotein modifi cations that promote lipoprotein uptake by macrophages ( 69,79,116,120 ).…”