Abstract
Oxysterols, and particularly 7-ketocholesterol, appear to be strongly involved in the physiopathology of atherosclerosis. These molecules are suspected to be cytotoxic to the cells of the vascular wall and monocytes/macrophages, particularly by inducing apoptosis. Previous studies have demonstrated that 7-ketocholesterol-induced apoptosis is triggered by a sustained increase of cytosolic-free Ca2+, which elicits the mitochondrial pathway of apoptosis by activation of the calcium-dependent phosphatase calcineurin, leading to dephosphorylation of the 'BH3 only' protein BAD. However, thorough study of the results suggests that other pathways are implicated in 7-ketocholesterol-induced cytotoxicity. In this study, we demonstrate the involvement of two other calcium-dependent pathways during 7-ketocholesterol-induced apoptosis. The activation of the MEK-->ERK pathway by the calcium-dependent tyrosine kinase PYK 2, a survival pathway which delays apoptosis as shown by the use of the MEK inhibitor U0126, and a pathway involving another pro-apoptotic BH3 only protein, Bim. Indeed, 7-ketocholesterol treatment of human monocytic THP-1 cells induces the release of Bim-LC8 from the microtubule-associated dynein motor complex, and its association with Bcl-2. Therefore, it appears that 7-ketocholesterol-induced apoptosis is a complex phenomenon resulting from calcium-dependent activation of several pro-apoptotic pathways and also one survival pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Calcium / metabolism*
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Carrier Proteins / drug effects
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Carrier Proteins / metabolism
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Cells, Cultured
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Discoidin Domain Receptor 1
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Dyneins / drug effects
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Dyneins / metabolism
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Focal Adhesion Kinase 2
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Humans
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Ketocholesterols / metabolism*
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Ketocholesterols / pharmacology
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MAP Kinase Kinase 1 / antagonists & inhibitors
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MAP Kinase Kinase 1 / metabolism
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MAP Kinase Kinase 2 / antagonists & inhibitors
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MAP Kinase Kinase 2 / metabolism
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Membrane Proteins / drug effects
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Membrane Proteins / metabolism
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Monocytes / metabolism
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Phosphorylation
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Protein Transport / drug effects
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / drug effects
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptor Protein-Tyrosine Kinases / metabolism
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Signal Transduction
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bcl-Associated Death Protein
Substances
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Apoptosis Regulatory Proteins
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BAD protein, human
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Carrier Proteins
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Enzyme Inhibitors
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Ketocholesterols
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Membrane Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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bcl-Associated Death Protein
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MAP2K2 protein, human
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DDR1 protein, human
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Discoidin Domain Receptor 1
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Protein-Tyrosine Kinases
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Receptor Protein-Tyrosine Kinases
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Focal Adhesion Kinase 2
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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Dyneins
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7-ketocholesterol
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Calcium