title: Oxidized low density lipoprotein induces cyclin A synthesis. Involvement of ERK, JNK and NFkappaB.
abstract: The cytotoxicity of oxidized LDL (OxLDL) towards different cell types of the arterial wall results in atherosclerotic plaque fissuring or rupture. The effects of OxLDL on cyclins A, E and D1 levels were investigated in human fibroblasts. A 24h incubation with Cu(2+)-oxidized (CuLDL) or monocyte-oxidized LDL (M-LDL), within the range of 10-50μg ApoB/ml, increased the intracellular level of cyclin A, both in the nuclear and in the cytoplasmic fraction. This increase is due to a stimulation of cyclin A mRNA synthesis, and cycloheximide had a preventive effect. The CuLDL-induced rise in cyclin A was accompanied by an augmentation of reactive oxygen species ROS and of lipid peroxidation end products. Furthermore, this effect was reproduced by the lipid extract of CuLDL and prevented by the antioxidant vitamin E, demonstrating the role of oxidized lipids and the involvement of oxidative stress. In addition, the use of specific inhibitors indicated that the increase in cyclin A involved ERK/JNK kinases and NFkappaB transcription factor. The augmentation of cyclin A was observed not only in fibroblasts but also in other cell types such as macrophages, T lymphocytes, endothelial and smooth muscle cells. Since cyclin A has been shown to be involved in cell cycle arrest, the described phenomenon might be related to the harmful effect of OxLDL, leading to plaque rupture.
authors.affiliation: Laboratoire de Biochimie, CHU Nord, Place Victor Pauchet, Amiens, France. maziere.cecile@chu-amiens.fr
authors.forename: Cécile
authors.initials: C
authors.lastname: Mazière
authors.forename: Eric
authors.initials: E
authors.lastname: Trécherel
authors.forename: Jérôme
authors.initials: J
authors.lastname: Ausseil
authors.forename: Christophe
authors.initials: C
authors.lastname: Louandre
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Mazière
mesh_terms: D000818:Animals; D019925:Cyclin A / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D019169:Jurkat Cells; D015227:Lipid Peroxidation; D008055:Lipids / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D013997:Time Factors; D020298:U937 Cells
chemical_list: D019925:Cyclin A; D008055:Lipids; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C099252:oxidized low density lipoprotein; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4