Potential Role for Ceramide in Mitogen-activated Protein Kinase Activation and Proliferation of Vascular Smooth Muscle Cells Induced by Oxidized Low Density Lipoprotein
| Autor: | Martine Chatelut, Jean-Claude Thiers, Guy Laurent, Isabelle Escargueil-Blanc, Thierry Levade, Pieraggi Mt, Nathalie Augé, Anne Nègre-Salvayre, Nathalie Andrieu-Abadie, Isabelle Lajoie-Mazenc, Robert Salvayre, Jean-Pierre Jaffrézou, Isabelle Suc |
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| Rok vydání: | 1998 |
| Předmět: |
MAPK/ERK pathway
Ceramide Vascular smooth muscle Biology Biochemistry Muscle Smooth Vascular chemistry.chemical_compound Animals Kinase activity Autocrine signalling Protein kinase A Molecular Biology Cells Cultured Cell Biology Sphingomyelins Cell biology Enzyme Activation Lipoproteins LDL Kinetics Sphingomyelin Phosphodiesterase chemistry Mitogen-activated protein kinase Calcium-Calmodulin-Dependent Protein Kinases biology.protein Cattle lipids (amino acids peptides and proteins) Signal transduction Oxidation-Reduction Cell Division Thymidine |
| Zdroj: | Journal of Biological Chemistry. 273:12893-12900 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.273.21.12893 |
| Popis: | Proliferation of vascular smooth muscle cells (SMC) is a hallmark in the pathogenesis of atherosclerotic lesions. Mildly oxidized low density lipoproteins (UV-oxLDL), which are mitogenic to cultured AG-08133A SMC, activate the sphingomyelin (SM)-ceramide pathway. We report here the following. (i) UV-oxLDL elicited a biphasic and sustained activation of MBP kinase activity, phosphorylation and nuclear translocation of p44/42 mitogen-activated protein kinase (MAPK), and [3H]thymidine incorporation, which were inhibited by PD-098059, a MAPK kinase inhibitor. (ii) The use of preconditioned media (from SMC pre-activated by UV-oxLDL) transferred to native SMC and blocking antibodies against growth factors suggest that UV-oxLDL-induced activation of MAPK and [3H]thymidine incorporation seem to be independent of any autocrine secretion of growth factors. (iii) UV-oxLDL-induced activation of a neutral sphingomyelinase, SM hydrolysis, ceramide production, and [3H]thymidine incorporation were inhibited by two serine-protease inhibitors (serpins), suggesting that a serpin-sensitive proteolytic pathway is involved in the activation of the SM-ceramide signaling pathway. (iv) UV-oxLDL-induced MAPK activation and [3H]thymidine incorporation were mimicked by ceramide generated in the plasma membrane by bacterial sphingomyelinase treatment or by addition of the permeant C2-ceramide. Serpins did not inhibit the MAPK activation and [3H]thymidine incorporation induced by C2-ceramide, indicating that activation of the MAPK and [3H]thymidine incorporation is subsequent to the stimulation of the SM-ceramide pathway. Taken together, these data suggest that mitogenic concentrations of UV-oxLDL are able to stimulate the SM-ceramide pathway through a protease-dependent mechanism and activate p44/42 MAPK, leading to proliferation of vascular SMC. |
| Databáze: | OpenAIRE |
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