Chemistry and Physics of Lipids

1998

DOI: 10.1016/s0009-3084(97)00095-9

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Strong increase in hydroxy fatty acids derived from linoleic acid in human low density lipoproteins of atherosclerotic patients

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,

Gerhard Spiteller

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³

et al.

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Atherogenic Lipids Specifically Increase Cx3cl1 and Cx3cr1 E1

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Cited by 123 publications

(102 citation statements)

References 36 publications

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“…SMC are the major non-leukocyte cell type detected in plaques at all stages of atherosclerosis (41,42), yet how these cells contribute to atherogenesis remains unclear. In this regard we show that oxLDL and oxidized linoleic acidcontaining lipids 9-HODE and 13-HODE, which are present at high concentrations in human atherosclerotic plaque (21)(22)(23), specifically and rapidly up-regulated CX3CL1 and its receptor CX3CR1 on CASMCs, augmenting CX3CL1-dependent macrophage-CASMC adhesion. Interestingly, oxLDL and oxidized linoleic acid lipids did not directly induce CX3CL1 but activated a TNF␣-NF-B-dependent autocrine loop.…”

Section: Discussionmentioning

confidence: 83%

“…Expression of CX3CL1 was increased by 7-15% by unmodified LDL or two bioactive arachidonic acid-containing phospholipid components of LDL, POV-PC and PGPC, which are found in atherosclerotic plaque (25), but this did not reach statistical significance. In contrast, oxLDL and either 9-HODE or 13-HODE, two oxidized linoleic acid-derived components of oxLDL found free at high concentrations in plaque (21)(22)(23), all increased the frequency of CX3CL1 ϩ and CX3CR1 ϩ cells (Figs. 1, A and B).…”

Section: Atherogenic Lipids Specifically Increase Cx3cl1 and Cx3cr1 Ementioning

confidence: 99%

“…In atherosclerosis, both cell types are exposed to atherogenic lipids (3) that could affect gene expression and function. In this regard we have shown that oxLDL and its bioactive oxidized linoleic acid metabolites deposited in human plaque, 9-HODE (9-hydroxy-10E,12Z-octadecadienoic acid ester) and 13-HODE (13-hydroxy-9Z,11E-octadecadienoic acid ester) (21)(22)(23), specifically induce differentiation of human CX3CR1 low monocytes to CX3CR1 high macrophages that strongly adhere to CASMCs under static conditions in a CX3CR1-dependent manner (24).…”

mentioning

confidence: 99%

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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

³

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 ...

“…SMC are the major non-leukocyte cell type detected in plaques at all stages of atherosclerosis (41,42), yet how these cells contribute to atherogenesis remains unclear. In this regard we show that oxLDL and oxidized linoleic acidcontaining lipids 9-HODE and 13-HODE, which are present at high concentrations in human atherosclerotic plaque (21)(22)(23), specifically and rapidly up-regulated CX3CL1 and its receptor CX3CR1 on CASMCs, augmenting CX3CL1-dependent macrophage-CASMC adhesion. Interestingly, oxLDL and oxidized linoleic acid lipids did not directly induce CX3CL1 but activated a TNF␣-NF-B-dependent autocrine loop.…”

Section: Discussionmentioning

confidence: 83%

“…Expression of CX3CL1 was increased by 7-15% by unmodified LDL or two bioactive arachidonic acid-containing phospholipid components of LDL, POV-PC and PGPC, which are found in atherosclerotic plaque (25), but this did not reach statistical significance. In contrast, oxLDL and either 9-HODE or 13-HODE, two oxidized linoleic acid-derived components of oxLDL found free at high concentrations in plaque (21)(22)(23), all increased the frequency of CX3CL1 ϩ and CX3CR1 ϩ cells (Figs. 1, A and B).…”

Section: Atherogenic Lipids Specifically Increase Cx3cl1 and Cx3cr1 Ementioning

confidence: 99%

“…In atherosclerosis, both cell types are exposed to atherogenic lipids (3) that could affect gene expression and function. In this regard we have shown that oxLDL and its bioactive oxidized linoleic acid metabolites deposited in human plaque, 9-HODE (9-hydroxy-10E,12Z-octadecadienoic acid ester) and 13-HODE (13-hydroxy-9Z,11E-octadecadienoic acid ester) (21)(22)(23), specifically induce differentiation of human CX3CR1 low monocytes to CX3CR1 high macrophages that strongly adhere to CASMCs under static conditions in a CX3CR1-dependent manner (24).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

³

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

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 ...

“…Jira et al (44,45), in fact, have reported increases in HODEs in LDL in diseases associated with increased oxidative stress, such as rheumatoid arthritis (44) and atherosclerosis (45). In obese type 2 diabetic patients, plasma 9-and 13-HODE levels are decreased by troglitazone therapy (46), but no information is available regarding plasma or lipoprotein-related HODE concentrations in T1DM.…”

Section: Discussionmentioning

confidence: 99%

Increased methionine sulfoxide content of apoA-I in type 1 diabetes

¹

,

²

,

³

et al. 2008

Journal of Lipid Research

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Cardiovascular disease is a major cause of morbidity and premature mortality in diabetes. HDL plays an important role in limiting vascular damage by removing cholesterol and cholesteryl ester hydroperoxides from oxidized low density lipoprotein and foam cells. Methionine (Met) residues in apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, reduce peroxides in HDL lipids, forming methionine sulfoxide [Met(O)]. We examined the extent and sites of Met(O) formation in apoA-I of HDL isolated from plasma of healthy control and type 1 diabetic subjects to assess apoA-I exposure to lipid peroxides and the status of oxidative stress in the vascular compartment in diabetes. Three tryptic peptides of apoA-I contain Met residues: Q 84 -M 86 -K 88 , W 108 -M 112 -R 116 , and L 144 -M 148 -R 149 . These peptides and their Met(O) analogs were identified and quantified by mass spectrometry. Relative to controls, Met(O) formation was significantly increased at all three locations (Met 86 , Met 112 , and Met 148 ) in diabetic patients. The increase in Met(O) in the diabetic group did not correlate with other biomarkers of oxidative stress, such as N : -malondialdehyde-lysine or N : -(carboxymethyl)lysine, in plasma or lipoproteins. The higher Met(O) content in apoA-I from diabetic patients is consistent with increased levels of lipid peroxidation products in plasma in diabetes. Using the methods developed here, future studies can address the relationship between Met(O) in apoA-I and the risk, development, or progression of the vascular complications of diabetes.-Brock, J.

“…Presumably, diet and age would impact on the loading of lipoproteins with oxylipids, as indicated by the work of Spiteller [2][3][4]. Body habitus probably plays a role, too.…”

Section: Discussionmentioning

confidence: 99%

Heparin, lipoproteins, and oxygenated fatty acids in blood: A cautionary note

et al. 2007

Prostaglandins, Leukotrienes and Essential Fatty Acids

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We measured 16 nonesterified oxygenated fatty acid derivatives (oxylipids) in plasmas from 7 human subjects. Two arterial samples from each subject were analyzed, drawn approximately two hours apart. We observed a marked increase in levels of most oxylipids in the second sample, as high as 470 fold. Between the first and second sample, subjects received approximately 800-1,000 IU of heparin to prevent clotting in intravascular catheters. We postulate that heparin activated lipoprotein lipases, which, in turn, released oxylipids from triglycerides and phospholipids in plasma lipoproteins. Some of that lipolysis may have occurred during sample storage. Measurements of nonesterified lipids in human plasma may be distorted if heparin is administered to subjects before blood is drawn and if lipase inhibitors are omitted from stored samples.

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