Abstract
Matrix metalloproteinase-1 (MMP-1) secreted by macrophages potentially contributes to plaque rupture. Because large quantities of immunoglobulin G and ICs (ICs), including low density lipoprotein-containing ICs (LDL-ICs), are present in atherosclerotic lesions, we examined the effect of LDL-ICs on macrophage MMP-1 expression. With the use of ICs prepared with human LDL and rabbit anti-LDL antiserum, our enzyme-linked immunosorbent assays and Northern blots showed that MMP-1 secretion and expression by U937 histiocytes were induced by LDL-ICs. Furthermore, our results showed that blocking of Fc-gamma receptor I and II (FcgammaRI and FcgammaRII) inhibited 70% and 55%, respectively, of the LDL-IC-induced secretion of MMP-1. Finally, our data showed that both PD98059, an inhibitor of the mitogen-activated protein kinase pathway, and Ro-31-2880, an inhibitor of protein kinase C, inhibited LDL-IC-stimulated MMP-1 secretion in a dose-dependent manner, with 96% and 95% inhibition, respectively, at the respective doses of 50 micromol/L and 80 nmol/L. In conclusion, this study demonstrated for the first time that LDL-ICs induce macrophage MMP-1 secretion by cocross-linking FcgammaRI and FcgammaRII and triggering a protein kinase C-dependent mitogen-activated protein kinase pathway. These results suggest that LDL-ICs and other ICs localized in atherosclerotic plaques may be potent stimulators for macrophage MMP-1 expression and may contribute to plaque rupture and acute coronary events.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antibodies, Anti-Idiotypic / immunology
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Antibodies, Monoclonal / pharmacology
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Antigen-Antibody Complex / immunology*
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Antigen-Antibody Complex / pharmacology
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Antigens, CD / immunology*
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Arteriosclerosis / enzymology
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Arteriosclerosis / immunology
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Collagenases / analysis
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Flavonoids / pharmacology
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Humans
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Immunoglobulin G / immunology
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Immunoglobulin G / pharmacology
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Lipoproteins, LDL / immunology*
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Lipoproteins, LDL / pharmacology
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Macrophages / drug effects
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Macrophages / enzymology*
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Matrix Metalloproteinase 1 / biosynthesis
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Matrix Metalloproteinase 1 / metabolism*
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism
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Receptors, IgG / antagonists & inhibitors
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Receptors, IgG / immunology*
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Tissue Inhibitor of Metalloproteinase-1 / antagonists & inhibitors
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Tissue Inhibitor of Metalloproteinase-1 / metabolism
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U937 Cells
Substances
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Antibodies, Anti-Idiotypic
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Antibodies, Monoclonal
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Antigen-Antibody Complex
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Antigens, CD
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Enzyme Inhibitors
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Fc gamma receptor IIA
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Flavonoids
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Immunoglobulin G
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Lipoproteins, LDL
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Receptors, IgG
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Tissue Inhibitor of Metalloproteinase-1
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anti-IgG
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oxidized low density lipoprotein
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Protein Kinase C
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Mitogen-Activated Protein Kinases
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Collagenases
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Matrix Metalloproteinase 1
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one