Abstract
7-Ketocholesterol is a component of oxidized LDL, which plays a central role in atherosclerosis. It is a potent inducer of cell death towards a wide number of cells involved in atherosclerosis. In this study, it is reported that 7-ketocholesterol treatment induces an increase of cytosolic-free Ca2+ in THP-1 monocytic cells. This increase is correlated with the induction of cytotoxicity as suggested from experiments using the Ca2+ channel blockers verapamil and nifedipine. This 7-ketocholesterol-induced apoptosis appears to be associated with the dephosphorylation of serine 75 and serine 99 of the proapoptotic protein Bcl-2 antagonist of cell death (BAD). We demonstrated that this dephosphorylation results mainly from the activation of calcium-dependent phosphatase calcineurin by the oxysterol-induced increase in Ca2+. Moreover, this Ca2+ increase appears related to the incorporation of 7-ketocholesterol into lipid raft domains of the plasma membrane, followed by the translocation of transient receptor potential calcium channel 1, a component of the store operated Ca2+ entry channel, to rafts.
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Abbreviations
- BAD:
-
Bcl-2 antagonist of cell death
- LRD:
-
lipid raft domain
- TRPC-1:
-
transient receptor potential calcium channel 1
- SOC:
-
store operated calcium
- 7-keto:
-
7-ketocholesterol
- CsA:
-
cyclosporin A
- Nif:
-
nifedipine
- Vera:
-
verapamil
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Acknowledgements
This work was supported by the University of Bourgogne, the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Conseil Régional de Bourgogne. We are grateful to Jonathan Ewing for reviewing the English version of this manuscript.
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Berthier, A., Lemaire-Ewing, S., Prunet, C. et al. Involvement of a calcium-dependent dephosphorylation of BAD associated with the localization of Trpc-1 within lipid rafts in 7-ketocholesterol-induced THP-1 cell apoptosis. Cell Death Differ 11, 897–905 (2004). https://doi.org/10.1038/sj.cdd.4401434
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DOI: https://doi.org/10.1038/sj.cdd.4401434
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