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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 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 (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.

SUBMITTER: Boyanovsky BB

PROVIDER: S-EPMC2656657 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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

Boyanovsky Boris B BB Shridas Preetha P Simons Michael M van der Westhuyzen Deneys R DR Webb Nancy R NR

Journal of lipid research 20081203 4

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 internalizat ...[more]

PMID: 19056705

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Project description:ObjectiveWe previously demonstrated that nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) mediates increased monocyte priming and chemotaxis under conditions of diabetic metabolic stress, and emerging data indicate that group VIA phospholipase A2 (iPLA2β) also participates in regulating monocyte chemotaxis. Here, we examined relationships between iPLA2β expression and Nox4 action in mouse peritoneal macrophages subjected to diabetic metabolic stress.Approach and resultsIncreased iPLA2β expression and activity were observed in macrophages from low-density lipoprotein receptor knockout mice that were fed a high-fat diet, and this was associated with time-dependent increases in atherosclerotic lesion size and macrophage content. Incubating macrophages with 30 mmol/L D-glucose, 100 μg/mL low-density lipoprotein, or both (D-glucose+low-density lipoprotein) induced a robust increase in iPLA2β expression and activity and in cell migration in response to monocyte chemoattractant protein-1. The increases in iPLA2β activity and cell migration were prevented by a bromoenol lactone iPLA2β suicide inhibitor or an iPLA2β antisense oligonucleotide. Incubating macrophages under conditions that mimic diabetic metabolic stress ex vivo resulted in increased Nox4 expression and activity and hydrogen peroxide generation compared with controls. Bromoenol lactone prevented those effects without affecting Nox2 expression. Nox4 inhibition eliminated diabetic metabolic stress-induced acceleration of macrophage migration. Lysophosphatidic acid restored Nox4 expression, hydrogen peroxide generation, and migration to bromoenol lactone-treated cells, and a lysophosphatidic acid receptor antagonist abrogated iPLA2β-mediated increases in Nox4 expression.ConclusionsTaken together, these observations identify iPLA2β and lysophosphatidic acid derived from its action as critical in regulating macrophage Nox4 activity and migration in the diabetic state in vivo and under similar conditions ex vivo.

Dataset Information

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

Publications

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

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