7-ketocholesterol incorporation into sphingolipid/cholesterol-enriched (lipid raft) domains is impaired by vitamin E: a specific role for alpha-tocopherol with consequences on cell death.
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 gamma-tocopherol, the alpha-tocopherol vitamin E form was found to prevent 7-ketocholesterol-mediated apoptosis of A7R5 smooth muscle cells. To be operative, alpha-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 alpha-tocopherol resulted in the redistribution of 7-ketocholesterol out of the sphingolipid/cholesterol-enriched (lipid raft) domains. In turn, fewer amounts of alpha-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 alpha-tocopherol, but not gamma-tocopherol pretreatment.
INSERM UMR866 and Université de Bourgogne, F 21079 Dijon, France.
Marie-Charlotte
MC
Royer
Stéphanie
S
Lemaire-Ewing
Catherine
C
Desrumaux
Serge
S
Monier
Jean-Paul
JP
Pais de Barros
Anne
A
Athias
Dominique
D
Néel
Laurent
L
Lagrost
D001011:Aorta; D016923:Cell Death / Q000502:physiology*; D002460:Cell Line; D002463:Cell Membrane Permeability; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007653:Ketocholesterols / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism*; D008564:Membrane Potentials; D051336:Mitochondrial Membranes / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D010084:Oxidation-Reduction; D013107:Sphingolipids / Q000378:metabolism*; D024505:Tocopherols / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology*; D024502:alpha-Tocopherol / Q000378:metabolism*
D007653:Ketocholesterols; D013107:Sphingolipids; D014810:Vitamin E; D002784:Cholesterol; D006861:Hydrogen Peroxide; D024502:alpha-Tocopherol; C003001:7-ketocholesterol; D024505:Tocopherols