Abstract
Accelerated atherosclerosis is a major co-morbid condition in autoimmune diseases. Monocytes are the main immune cell involved in atherosclerosis initiation. We hypothesized that dysfunctional, pro-inflammatory HDL (piHDL), which occurs in approximately half of SLE patients, might directly influence monocyte gene expression and function. SLE subjects were stratified into three groups: 1) carotid artery plaque+piHDL+,2) plaque-piHDL+,and 3) plaque-piHDL- (n=18/group). PDGFRβ was upregulated in primary monocytes from plaque+piHDL+patients and in THP-1 cells acutely treated in vitro with piHDL compared to normal HDL. THP-1 chemotaxis was enhanced after treatment with piHDL versus normal HDL. Abnormal migration was restored to normal levels by treatment with imatinib or an apoJ mimetic peptide. Increased piHDL-mediated TNFα protein levels were reduced with both inhibitors. Dysfunctional piHDL directly influences expression of a small number of transcripts and proteins, and piHDL inhibition through reducing piHDL oxidation or blocking PDGFRβ kinase activity restored normal monocyte chemotaxis.
Copyright © 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Apolipoprotein A-I / chemistry
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Benzamides
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Carotid Artery Diseases / blood
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Carotid Artery Diseases / etiology
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Carotid Artery Diseases / pathology
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Cell Line, Tumor
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Cell Movement / drug effects
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Chemokine CCL2 / genetics
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Chemokine CCL2 / metabolism
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Chemotaxis / drug effects*
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Cholesterol / blood
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Clusterin / chemistry
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Female
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Gene Expression / drug effects
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Gene Expression / genetics
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Heart Diseases / epidemiology
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Humans
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Imatinib Mesylate
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Lipoproteins, HDL / blood
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Lipoproteins, HDL / pharmacology*
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Lupus Erythematosus, Systemic / blood
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Lupus Erythematosus, Systemic / complications
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Lupus Erythematosus, Systemic / diagnosis
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Lupus Erythematosus, Systemic / metabolism*
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Middle Aged
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Molecular Mimicry
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Monocytes / cytology
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Monocytes / drug effects
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Monocytes / metabolism*
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Peptides / pharmacology
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Piperazines / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Pyrimidines / pharmacology
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Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
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Receptor, Platelet-Derived Growth Factor beta / genetics*
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Risk Factors
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Severity of Illness Index
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Apolipoprotein A-I
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Benzamides
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CCL2 protein, human
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CLU protein, human
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Chemokine CCL2
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Clusterin
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Lipoproteins, HDL
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Peptides
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Tumor Necrosis Factor-alpha
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Imatinib Mesylate
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Cholesterol
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Receptor, Platelet-Derived Growth Factor beta