Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator–activated receptor γ

Han, Ki Hoon; Chang, Mi Kyung; Boullier, Agnès; Green, Simone R.; Li, Andrew; Glass, Christopher K.; Quehenberger, Oswald

doi:10.1172/jci10052

Cited by 170 publications

(114 citation statements)

References 57 publications

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“…Recent data suggest that oxidized lipids may act in part by regulating production and function of chemokines and chemokine receptors expressed by cells in plaque (24,(35)(36)(37)(38). Although chemokines and chemokine receptors involved in atherosclerosis are predominantly expressed by leukocytes (1,39), recent data show that they are also expressed by other cell types such as SMC (40).…”

Section: Discussionmentioning

confidence: 99%

Atherogenic Lipids Induce Adhesion of Human Coronary Artery Smooth Muscle Cells to Macrophages by Up-regulating Chemokine CX3CL1 on Smooth Muscle Cells in a TNFα-NFκB-dependent Manner

Barlic¹,

Zhang²,

Murphy

2007

Journal of Biological Chemistry

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Recent genetic evidence has implicated the adhesive chemokine CX3CL1 and its leukocyte receptor CX3CR1 in atherosclerosis. We previously proposed a mechanism involving foam cell anchorage to vascular smooth muscle cells because: 1) CX3CL1 and CX3CR1 are expressed by both cell types in mouse and human atherosclerotic lesions; 2) foam cells are reduced in lesions in cx3cr1 ؊/؊ apoE ؊/؊ mice; and 3) proatherogenic lipids (oxidized low density lipoprotein [oxLDL] and oxidized linoleic acid derivatives) induce adhesion of primary human macrophages to primary human coronary artery smooth muscle cells (CASMCs) in vitro in a macrophage CX3CR1-dependent manner. Here we analyze this concept further by testing whether atherogenic lipids regulate expression and function of CX3CL1 and CX3CR1 on CASMCs. We found that both oxLDL and oxidized linoleic acid derivatives indirectly up-regulated CASMC CX3CL1 at both the protein and mRNA levels through an autocrine feedback loop involving tumor necrosis factor ␣ production and NF-B signaling. Oxidized lipids also up-regulated CASMC CX3CR1 but through a different mechanism. Oxidized lipid stimulation also increased adhesion of macrophages to CASMCs when CASMCs were stimulated prior to assay, and a synergistic pro-adhesive effect was observed when both cell types were prestimulated. Selective inhibition with a CX3CL1-specific blocking antibody indicated that adhesion was strongly CASMC CX3CL1-dependent. These findings support the hypothesis that CX3CR1 and CX3CL1 mediate heterotypic anchorage of foam cells to CASMCs in the context of atherosclerosis and suggest that this chemokine/chemokine receptor pair may be considered as a pro-inflammatory target for therapeutic intervention in atherosclerotic cardiovascular disease.Atherosclerosis involves a complex interplay of inflammatory cells, vascular elements, and lipoproteins coordinated by adhesion molecules, cytokines, and chemokines (1, 2). Oxidation of low density lipoprotein (LDL) 3 and its accumulation in the subendothelial space are key initiating events that promote accumulation of leukocytes and other cell types that organize over time to form plaque (3). Leukocyte recruitment mechanisms are unclear; however, recent genetic data from mouse and man have implicated members of the chemokine family, a large group of leukocyte chemoattractants active at G proteincoupled receptors (4). Of these, the evidence for CX3CL1 (also known as fractalkine) and its receptor CX3CR1 is particularly strong (5-10). CX3CL1 is an atypical multimodular chemokine that exists both in membrane-tethered and shed forms. The immobilized form consists of a chemokine domain anchored to the plasma membrane through an extended mucin-like stalk, a transmembrane helix, and an intracellular domain (11). Transmembrane CX3CL1 is an adhesion molecule that mediates integrin-independent cell capture by binding to CX3CR1 on target cells (12). Following protease-mediated release of the chemokine domain (13, 14), CX3CL1 may also promote classical chemotactic responses of ...

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Section: Discussionmentioning

confidence: 99%

Atherogenic Lipids Induce Adhesion of Human Coronary Artery Smooth Muscle Cells to Macrophages by Up-regulating Chemokine CX3CL1 on Smooth Muscle Cells in a TNFα-NFκB-dependent Manner

Barlic¹,

Zhang²,

Murphy

2007

Journal of Biological Chemistry

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“…Inhibition was more pronounced with extensively modified LDL in a dose-dependent manner and is hypothesized to block reverse transmigration and accelerating atherosclerosis by causing monocytes to remain in the intima allowing for maturation into macrophages. 18 The CCR2 gene is located at 3p21.31 and contains three exons. This gene is not well annotated and none of the six single-nucleotide polymorphisms and one deletion/ insertion listed in the National Center for Biotechnology Information database has been genotyped in HapMap.…”

Section: Discussionmentioning

confidence: 99%

Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI Family Heart Study follow-up examination

et al. 2007

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Atherogenesis is a chronic inflammatory process. Critical in the inflammation process is monocyte chemoattractant protein-1 (MCP-1). To locate genomic regions that affect circulating MCP-1 levels, a genome-wide linkage scan was conducted in a sample of whites and blacks. Phenotype and genetic marker data were available for 2501 white and 513 black participants in the National Heart Lung Blood Institute Family Heart Study follow-up examination. Heritability for MCP-1 was 0.37 in whites and 0.47 in blacks after adjusting for the effects of sex, age, age-sex interaction, smoking status, lifetime smoking exposure (pack-years) and field center. Significant linkage was observed for MCP-1 in a combined black and white sample on chromosome 3 (logarithm of the odds ratio (LOD) ¼ 3.5 at 78 cM, P ¼ 0.0001) and suggestive linkage was observed in whites on chromosome 5 (LOD ¼ 1.8 at 128 cM, P ¼ 0.002). Located under the linkage peak on chromosome 3 is the chemokine receptor gene cluster, including CCR2, the receptor for MCP-1. This study provides preliminary evidence linking genetic variation in a receptor to circulating levels of its ligand, as previously demonstrated for the low-density lipoprotein receptor. Further characterization of these chromosomal regions is needed to identify the functional mutations associated with circulating levels of MCP-1.

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“…This method did not injure macrophages as determined by trypan blue exclusion and phase contrast micrographic inspection. The amount of CCR2 protein on the cell surface was estimated by flow cytometry as described [29]. CCR2 surface expression was expressed as specific mean fluorescence intensity (MFI), obtained by subtracting the MFI of control cells from that of cells labeled with anti-CCR2 antibody.…”

Section: Analysis Of Cell Surface Ccr2mentioning

confidence: 99%

Glycated LDL increases monocyte CC chemokine receptor 2 expression and monocyte chemoattractant protein-1-mediated chemotaxis

et al. 2008

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Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator–activated receptor γ

Cited by 170 publications

References 57 publications

Atherogenic Lipids Induce Adhesion of Human Coronary Artery Smooth Muscle Cells to Macrophages by Up-regulating Chemokine CX3CL1 on Smooth Muscle Cells in a TNFα-NFκB-dependent Manner

Atherogenic Lipids Induce Adhesion of Human Coronary Artery Smooth Muscle Cells to Macrophages by Up-regulating Chemokine CX3CL1 on Smooth Muscle Cells in a TNFα-NFκB-dependent Manner

Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI Family Heart Study follow-up examination

Glycated LDL increases monocyte CC chemokine receptor 2 expression and monocyte chemoattractant protein-1-mediated chemotaxis

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