Abstract
Lectin-like oxidized LDL receptor-1 (LOX-1) is a newly identified receptor for oxidized LDL that is expressed by vascular cells. LOX-1 is upregulated in aortas of diabetic rats and thus may contribute to the pathogenesis of human diabetic atherosclerosis. In this study, we examined the regulation of human monocyte-derived macrophage (MDM) LOX-1 expression by high glucose and the role of LOX-1 in glucose-induced foam cell formation. Incubation of human MDMs with glucose (5.6 to 30 mmol/L) enhanced, in a dose- and time-dependent manner, LOX-1 gene and protein expression. Induction of LOX-1 gene expression by high glucose was abolished by antioxidants, protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), nuclear factor-kappaB (NF-kappaB), and activated protein-1 (AP-1) inhibitors. In human MDMs cultured with high glucose, increased expression of PKCbeta2 and enhanced phosphorylation of extracellular signal-regulated protein kinase 1/2 was observed. Activation of these kinases was inhibited by the antioxidant N-acetyl-L-cysteine (NAC) and by the PKCbeta inhibitor LY379196. High glucose also enhanced the binding of nuclear proteins extracted from human MDMs to the NF-kappaB and AP-1 regulatory elements of the LOX-1 gene promoter. This effect was abrogated by NAC and PKC/MAPK inhibitors. Finally, high glucose induced human macrophage-derived foam cell formation through a LOX-1-dependent pathway. Overall, these results demonstrate that high glucose concentrations enhance LOX-1 expression in human MDMs and that this effect is associated with foam cell formation. Pilot data showing that MDMs of patients with type 2 diabetes overexpress LOX-1 support the relevance of this work to human diabetic atherosclerosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / pharmacology
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Adult
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Aged
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Anti-Infective Agents / pharmacology
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Antioxidants / pharmacology
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Arteriosclerosis / etiology
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Arteriosclerosis / metabolism
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Curcumin / pharmacology
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Diabetes Mellitus, Type 2 / complications
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Enzyme Inhibitors / pharmacology
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Female
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Flavonoids / pharmacology
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Foam Cells / metabolism
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Foam Cells / pathology*
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Gene Expression Regulation / drug effects
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Glucose / pharmacology*
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Glycation End Products, Advanced / analysis
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Humans
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Hyperglycemia / genetics
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Hyperglycemia / metabolism*
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MAP Kinase Signaling System / drug effects
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Macrophages / drug effects*
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Macrophages / metabolism
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Macrophages / pathology
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Male
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Mesylates / pharmacology
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Middle Aged
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / physiology
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Nitriles
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Phosphorylation / drug effects
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism
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Protein Kinase C beta
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Protein Processing, Post-Translational / drug effects
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Pyrroles / pharmacology
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RNA, Messenger / biosynthesis
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Receptors, LDL / biosynthesis
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Receptors, LDL / genetics
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Receptors, LDL / physiology*
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Signal Transduction / drug effects
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Sulfones
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Transcription Factor AP-1 / antagonists & inhibitors
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Transcription Factor AP-1 / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate
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Anti-Infective Agents
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Antioxidants
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BAY 11-7085
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Enzyme Inhibitors
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Flavonoids
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Glycation End Products, Advanced
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Mesylates
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NF-kappa B
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Nitriles
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Pyrroles
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RNA, Messenger
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Receptors, LDL
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Sulfones
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Transcription Factor AP-1
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Tumor Necrosis Factor-alpha
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Protein Kinase C
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Protein Kinase C beta
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Curcumin
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Glucose
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Acetylcysteine