High-density lipoprotein and low-density lipoprotein-mediated signal transduction in cultured human skin fibroblasts

Möllers, Christoph; Drobnik, Wolfgang; Resink, Thérèse J.; Schmitz, Gerd

doi:10.1016/0898-6568(95)00041-m

Cited by 28 publications

(10 citation statements)

References 49 publications

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“…This phenomenon might be interpreted by the fact that the AP1 subunits are very sensitive to the redox state of the cell [20], by means of the conserved cysteine residues included in their DNA‐binding domains [21, 22]. Alternatively, native LDL might act via a signal‐transduction pathway: indeed, it has been reported that the LDL particle stimulates the production of diacylglycerol, induces the release of Ca 2+ from intracellular pools and activates protein kinase C in alveolar type II cells [23]and human fibroblasts [24]. Resink et al [25]also demonstrated that, in rat smooth muscle cells, native LDL stimulates the accumulation of inositol phosphates.…”

Section: Discussionmentioning

confidence: 99%

Copper and cell‐oxidized low‐density lipoprotein induces activator protein 1 in fibroblasts, endothelial and smooth muscle cells

et al. 1997

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The effect of cupric ion-or endothelial cell-oxidized low-density lipoproteins (LDL) on transcription factor API activation was investigated by electrophoretic mobility shift assay. Both oxidized LDL induced API activation in fibroblasts, endothelial and smooth muscle cells. This phenomenon was also observed in the presence of cycloheximide. a-Tocopherol, a lipophilic free radical scavenger, and TV-acetylcysteine, an hydrophilic antioxidant, partially inhibited the stimulatory effect of Cu 2+ -oxidized LDL. LDL modified by the mixture of the oxygen radicals OH-and 0 2 -, which generated lipid peroxidation products, also initiated API activation, whereas LDL modified by OH-alone, which did not lead to marked LDL lipid peroxidation, was ineffective. Thus, lipid peroxidation products seem at least partially involved in the activation mechanism. Since API activity is essential for the regulation of genes involved in cell growth and differentiation, our study suggests that the oxidative stress induced by oxidized LDL might be related to the fibroproliferative response observed in the atherosclerotic plaque. © 1997 Federation of European Biochemical Societies.

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Section: Discussionmentioning

confidence: 99%

Copper and cell‐oxidized low‐density lipoprotein induces activator protein 1 in fibroblasts, endothelial and smooth muscle cells

et al. 1997

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“…49 Activation of nuclear factor of activated T cells requires both the elevation of Ca 2ϩ and mobilization of protein kinase C. 50 As HDLs have been shown to be capable of inducing both these responses, 51,52 it was possible that the lack of effect on GM-CSF synthesis is by induction of the calcium-sensitive distal enhancer region, which could mask any inhibition of the proximal promoter region. To overcome this consideration, we compared the effect of HDLs on the TNFinducible expression of reporter genes controlled by the E-selectin and GM-CSF proximal promoters in transient transfection assays in HUVECs.…”

Section: Resultsmentioning

confidence: 99%

High-Density Lipoproteins Differentially Modulate Cytokine-Induced Expression of E-Selectin and Cyclooxygenase-2

Cockerill

Saklatvala

Ridley

et al. 1999

ATVB

116

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Abstract-Atherogenesis is a multifactorial chronic inflammatory disease in which low plasma levels of HDLs are a strong predictor of the condition. Although the mechanism of protection by HDLs is not precisely known, HDLs have been shown to influence many of the events involved in the development of atherosclerosis. Previously we have shown that HDLs inhibited the cytokine-induced expression of adhesion molecules (E-selectin, VCAM-1, and ICAM-1) by endothelial cells (ECs). As the complete transcriptional regulation of all 3 genes requires the NF-B family of transcription factors, we examined the effect of HDLs on activation of NF-B. We also investigated the effect of HDLs on 2 other cytokine-induced genes, granulocyte-macrophage colony-stimulating factor (GM-CSF) and cyclooxygenase (Cox-2; prostaglandin H 2 synthase, EC 0.1.14.99.1). E-selectin expression in response to tumor necrosis factor-␣ (TNF␣) was, as expected, inhibited in ECs that had been preincubated with HDLs. However, the level of secretion of GM-CSF in the same cultures was no different from control. In a similar manner, although HDLs had no effect on steady-state mRNA levels of GM-CSF, the levels of E-selectin were significantly inhibited by HDLs. In transient cotransfection experiments we found that HDLs inhibited the cytokine-induced expression of a reporter gene driven by the E-selectin proximal promoter (Ϫ383 to 80) but had no effect on the expression of a reporter gene driven under the control of the proximal promoter of GM-CSF (Ϫ627 to 28). As would be predicted from this differential response, HDLs did not influence the nuclear translocation or DNA binding of NF-B, or alter the kinetics of degradation and resynthesis of the inhibitory protein IB␣. We found that HDLs synergized with cytokine to enhance the expression of Cox-2 and induce the synthesis of its main EC product, prostacyclin (PGI 2 ), a potent inhibitor of platelet and leukocyte functions.In conclusion, HDL induces an antiinflammatory phenotype in cytokine-induced ECs, synergizing with cytokine to induce elevation of Cox-2 in addition to inhibiting adhesion molecule expression. Our studies show that these differential effects are mediated in a manner that is likely to be independent of NF-B per se. (Arterioscler Thromb Vasc Biol. 1999;19:910-917.)

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“…The cholesterol export kinetics during incubation of macrophages with HDL 3 was assessed for HDL 3 -dependent and -independent cholesterol efflux. For this, macrophages were loaded with acLDL for 2 days in the presence of 14 C-cholesterol as described (25)(26)(27). Cells were then washed and deloaded in the presence of HDL 3 for 12, 24, and 48 h, respectively.…”

Section: Kinetics Of Cholesterol Loading and Deloading In Human Macromentioning

confidence: 99%

ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport

Klucken

Büchler

Orsó

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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507

438

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Excessive uptake of atherogenic lipoproteins such as modified lowdensity lipoprotein complexes by vascular macrophages leads to foam cell formation, a critical step in atherogenesis. Cholesterol efflux mediated by high-density lipoproteins (HDL) constitutes a protective mechanism against macrophage lipid overloading. The molecular mechanisms underlying this reverse cholesterol transport process are currently not fully understood. To identify effector proteins that are involved in macrophage lipid uptake and release, we searched for genes that are regulated during lipid influx and efflux in human macrophages using a differential display approach. We report here that the ATP-binding cassette (ABC) transporter ABCG1 (ABC8) is induced in monocyte-derived macrophages during cholesterol influx mediated by acetylated low-density lipoprotein. Conversely, lipid efflux in cholesterol-laden macrophages, mediated by the cholesterol acceptor HDL 3, suppresses the expression of ABCG1. Immunocytochemical and flow cytometric analyses revealed that ABCG1 is expressed on the cell surface and in intracellular compartments of cholesterol-laden macrophages. Inhibition of ABCG1 protein expression using an antisense strategy resulted in reduced HDL 3-dependent efflux of cholesterol and choline-phospholipids. In a comprehensive analysis of the expression and regulation of all currently known human ABC transporters, we identified an additional set of ABC genes whose expression is regulated by cholesterol uptake or HDL 3-mediated lipid release, suggesting a potential function for these transporters in macrophage lipid homeostasis. Our results demonstrating a regulator function for ABCG1 in cholesterol and phospholipid transport define a biologic activity for ABC transporters in macrophages.

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High-density lipoprotein and low-density lipoprotein-mediated signal transduction in cultured human skin fibroblasts

Cited by 28 publications

References 49 publications

Copper and cell‐oxidized low‐density lipoprotein induces activator protein 1 in fibroblasts, endothelial and smooth muscle cells

Copper and cell‐oxidized low‐density lipoprotein induces activator protein 1 in fibroblasts, endothelial and smooth muscle cells

High-Density Lipoproteins Differentially Modulate Cytokine-Induced Expression of E-Selectin and Cyclooxygenase-2

ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport

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