7-Ketocholesterol Incorporation into Sphingolipid/Cholesterol-enriched (Lipid Raft) Domains Is Impaired by Vitamin E: A SPECIFIC ROLE FOR α-TOCOPHEROL WITH CONSEQUENCES ON CELL DEATH

• Published in: The Journal of biological chemistry 2009-06, Vol.284 (23), p.15826-15834
• Main Authors: Royer, Marie-Charlotte, Lemaire-Ewing, Stéphanie, Desrumaux, Catherine, Monier, Serge, Pais de Barros, Jean-Paul, Athias, Anne, Néel, Dominique, Lagrost, Laurent
• Format: Article
• Language: English
• Subjects: alpha-Tocopherol - metabolism; Aorta; Biochemistry; Biochemistry, Molecular Biology; Cell Death - physiology; Cell Line; Cell Membrane Permeability; Cholesterol - metabolism; Humans; Hydrogen Peroxide - metabolism; Ketocholesterols - metabolism; Life Sciences; Lipids and Lipoproteins: Metabolism, Regulation, and Signaling; Membrane Microdomains - metabolism; Membrane Potentials; Mitochondrial Membranes - physiology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - physiology; Oxidation-Reduction; Sphingolipids - metabolism; Tocopherols - metabolism; Vitamin E - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M808641200

Cholesterol oxides, in particular 7-ketocholesterol, are proatherogenic compounds that induce cell death in the vascular wall when localized in lipid raft domains of the cell membrane. Deleterious effects of 7-ketocholesterol can be prevented by vitamin E, but the molecular mechanism involved is unclear. In this study, unlike γ-tocopherol, the α-tocopherol vitamin E form was found to prevent 7-ketocholesterol-mediated apoptosis of A7R5 smooth muscle cells. To be operative, α-tocopherol needed to be added to the cells before 7-ketocholesterol, and its anti-apoptotic effect was reduced and even suppressed when added together or after 7-ketocholesterol, respectively. Both pre- and co-treatment of the cells with α-tocopherol resulted in the redistribution of 7-ketocholesterol out of the sphingolipid/cholesterol-enriched (lipid raft) domains. In turn, fewer amounts of α-tocopherol associated with lipid rafts on 7-ketocholesterol-pretreated cells compared with untreated cells, with no prevention of cell death in this case. In further support of the implication of lipid raft domains, the dephosphorylation/inactivation of Akt-PKB was involved in the 7-ketocholesterol-induced apoptosis. Akt-PKB dephosphorylation was prevented by α-tocopherol, but not γ-tocopherol pretreatment.