The Sphingomyelin-Ceramide Signaling Pathway Is Involved in Oxidized Low Density Lipoprotein-induced Cell Proliferation

Augé, Nathalie; Andrieu, Nathalie; Nègre‐Salvayre, Anne; Thiers, Jean-Claude; Levade, Thierry; Salvayre, Robert

doi:10.1074/jbc.271.32.19251

Cited by 120 publications

(105 citation statements)

References 48 publications

(41 reference statements)

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“…OxLDL-induced smooth muscle cell proliferation was mediated by sphingomyelinase-ceramide signaling pathway (Auge et al, 1996) with a possible involvement of fibroblast growth factor (Chai et al, 1996). Since smooth muscle cell proliferation was known to be a late stage response of atherosclerosis, oxLDL may aggravate the process of atherogenesis by increasing the number of smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

“…The whole oxLDL induced differentiation (Parhami et al, 1993), gene expression (Han et al, 1997), cytokine production (Thomas et al, 1994;Lipton et al, 1995), inhibition of the macrophage motility (Quinn et al, 1985), cytotoxicity (Dimmeler et al, 1997), inhibition of the nitric oxide-induced vasodilatation (Liao et al, 1995;Goss et al, 1997), and mitogenicity (Auge et al, 1995;Auge et al, 1996;Chai et al, 1996). Different components of oxLDL might play roles in these various biological activities.…”

Section: Discussionmentioning

confidence: 99%

“…Some of the functions were clearly contradictory with each other. OxLDL stimulated cell proliferation in smooth muscle cells (Auge et al, 1995;Auge et al, 1996;Chai et al, 1996) whereas it induced cell death in endothelial cells (Quinn, et al, 1985), smooth muscle cells (Nishio et al, 1996), or macrophages (Hardwick et al, 1996). However, it was difficult to explain why the oxLDL-induced cellular responses were contrary and which major contributor resulted in those responses.…”

Section: Introductionmentioning

confidence: 94%

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Oxidation-dependent effects of oxidized LDL: proliferation or cell death

Han

Pak²

1999

Exp Mol Med

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Oxidized low-density lipoprotein (oxLDL) induces a wide range of cellular responses to produce atherosclerotic lesion, but key factors determining the response are not understood. In this study, purified LDL was oxidized with copper sulfate, and its physical properties and the related biological responses were investigated. The average hydrodynamic diameter of the lightly oxidized LDL was approximately 25 nm and its Rf value relative to nLDL on agarose gel was between 1.0 and 1.25. The diameter of the extensively oxidized LDL was over 30 nm, the Rf value was over 2.0. A 24 h-exposure of resting RAW264.7 macrophage cells to 100 µ µ µ µg/ml of the lightly oxidized LDL induced proliferation and macrophage activation whereas the extensively oxidized LDL induced cell death at the same concentration. In contrast, 200 µ µ µ µg/ ml of oxLDL caused cell death regardless of oxidation degree. Short incubation (4-6 h) of the highly oxidized LDL (100 µ µ µ µg/ml) also resulted in cell proliferation. OxLDL-induced cell death showed mixed characteristics of apoptosis and/or necrosis depending on the strength and duration of the insult. These results suggest that cellular responses induced by oxLDL be dependent on the oxidation degree, the duration of exposure, and the concentration of oxLDL.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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Oxidation-dependent effects of oxidized LDL: proliferation or cell death

Han

Pak²

1999

Exp Mol Med

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“…Auge and colleagues demonstrated the critical role of the sphingomyelin-ceramide pathway in the oxidized low density lipoprotein (ox-LDL)-induced smooth muscle cell proliferation and atherogenesis (Auge et al, 1996). Lactosylceramide (LacCer)-mediated plaque formation involves aortic smooth muscle cell proliferation .…”

Section: Ceramide and Cardiovascular Disordersmentioning

confidence: 99%

Recent advances in the immunobiology of ceramide

Pandey

Murphy

Agrawal

2007

Experimental and Molecular Pathology

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Ceramide, a sphingosine-based lipid molecule, has emerged as a key regulator of a wide spectrum of biological processes such as cellular differentiation, proliferation, apoptosis and senescence. Sphingomyelinase-dependent hydrolysis of sphingomyelin, and de novo synthesis involving the coordinated action of serinepalmitoyl transferase and ceramide synthase, are the two major pathways involved in ceramide synthesis. Clustering of plasma membrane rafts into ceramide enriched platforms serves as an important transmembrane signaling mechanism for cell surface receptors. Ceramides have been implicated in apoptosis, stress-signaling cascades as well as ion channels. There is accumulating evidence that targeted manipulation of ceramide metabolism pathway has immense therapeutic potential and may eventually prove to be a boon in the design of novel strategies and development of innovative treatments for diverse conditions including cardiovascular diseases, cancer and Alzheimer's disease. As yet uncharacterized natural ceramide analogs and novel inhibitors of ceramide metabolism might prove to be potent drugs. In this review, we discuss significant advances that continue to provide intriguing insights into the complex cellular and molecular mechanisms underlying ceramide-mediated signaling cascades.

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“…Oxidized low density lipoproteins (oxLDL) 3 are generated in vitro by auto-oxidation in the presence of transition metals (1,2) or in vivo via cell-mediated mechanisms (3,4). OxLDL has been shown to be a powerful regulator of cell signaling in provoking various responses, among others, expression of adhesion molecules on endothelial cells (5), production of proinflammatory cytokines and growth factors by vascular cells (6), or proliferation and migration of vascular cells (7). In addition, oxLDL is both a potent chemoattractant for circulating monocytes (8) and a differentiating agent that promotes transition of macrophages to lipid-loaded foam cells (9).…”

mentioning

confidence: 99%

Dualism of Oxidized Lipoproteins in Provoking and Attenuating the Oxidative Burst in Macrophages: Role of Peroxisome Proliferator-Activated Receptor-γ

Fischer

Knethen

Brüne

2002

The Journal of Immunology

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Activation and deactivation of macrophages are of considerable importance during the development of various disease states, atherosclerosis among others. Macrophage activation is achieved by oxidized lipoproteins (oxLDL) and is determined by oxygen radical (ROS) formation. The oxidative burst was measured by flow cytometry and quantitated by oxidation of the redox-sensitive dye dichlorodihydrofluorescein diacetate. Short-time stimulation dose-dependently elicited ROS formation. Diphenylene iodonium prevented ROS formation, thus pointing to the involvement of a NAD(P)H oxidase in producing reduced oxygen species. In contrast, preincubation of macrophages with oxLDL for 16 h showed an attenuated oxidative burst upon a second contact with oxLDL. Taking into account that oxLDL is an established peroxisome proliferator-activated receptor-γ (PPARγ) agonist and considering the anti-inflammatory properties of PPARγ, we went on and showed that a PPARγ agonist such as ciglitazone attenuated ROS formation. Along that line, major lipid peroxidation products of oxLDL, such as 9- and 13-hydroxyoctadecadienoic acid, shared that performance. Supporting evidence that PPARγ activation accounted for reduced ROS generation came from studies in which proliferator-activated receptor response element decoy oligonucleotides, but not a mutated oligonucleotide, supplied in front of oxLDL delivery regained a complete oxidative burst upon cell activation. We conclude that oxLDL not only elicits an oxidative burst upon first contact, but also promotes desensitization of macrophages via activation of PPARγ. Desensitization of macrophages may have important consequences for the behavior of macrophages/foam cells in atherosclerotic lesions.

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The Sphingomyelin-Ceramide Signaling Pathway Is Involved in Oxidized Low Density Lipoprotein-induced Cell Proliferation

Abstract: Development of atherosclerosis is believed to involve proliferation of smooth muscle cells (SMC).

Cited by 120 publications

References 48 publications

Oxidation-dependent effects of oxidized LDL: proliferation or cell death

Oxidation-dependent effects of oxidized LDL: proliferation or cell death

Recent advances in the immunobiology of ceramide

Dualism of Oxidized Lipoproteins in Provoking and Attenuating the Oxidative Burst in Macrophages: Role of Peroxisome Proliferator-Activated Receptor-γ

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