Syndecan-4 mediates macrophage uptake of group V secretory phospholipase A2-modified LDL.
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.
Boyanovsky
Boris B
BB
Department of Internal Medicine, Endocrinology Division, University of Kentucky Medical Center, Lexington, KY 40536, USA.
Shridas
Preetha
P
Simons
Michael
M
van der Westhuyzen
Deneys R
DR
Webb
Nancy R
NR
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism; D001483:Base Sequence; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D054505:Group V Phospholipases A2 / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D010873:Pinocytosis / Q000187:drug effects; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D053670:Syndecan-3 / Q000378:metabolism; D053671:Syndecan-4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D002867:Chromones; D017931:DNA Primers; D008077:Lipoproteins, LDL; D009025:Morpholines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C508302:Sdc3 protein, mouse; C508306:Sdc4 protein, mouse; D053670:Syndecan-3; D053671:Syndecan-4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D054505:Group V Phospholipases A2