7-Ketocholesterol-induced apoptosis. Involvement of several pro-apoptotic but also anti-apoptotic calcium-dependent transduction pathways

• Published in: The FEBS journal 2005-06, Vol.272 (12), p.3093-3104
• Main Authors: Berthier, Arnaud, Lemaire-Ewing, Stéphanie, Prunet, Céline, Montange, Thomas, Vejux, Anne, Pais de Barros, Jean Paul, Monier, Serge, Gambert, Philippe, Lizard, Gérard, Néel, Dominique
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Apoptosis - physiology; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; bcl-Associated Death Protein; Blood vessels; Calcium; Calcium - metabolism; Carrier Proteins - drug effects; Carrier Proteins - metabolism; Cells, Cultured; Cholesterol; Discoidin Domain Receptor 1; Dyneins - drug effects; Dyneins - metabolism; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Focal Adhesion Kinase 2; Humans; Ketocholesterols - metabolism; Ketocholesterols - pharmacology; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - metabolism; MAP Kinase Kinase 2 - antagonists & inhibitors; MAP Kinase Kinase 2 - metabolism; Membrane Proteins - drug effects; Membrane Proteins - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Monocytes - metabolism; Phosphorylation; Protein Transport - drug effects; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - drug effects; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Signal Transduction
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2005.04723.x

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.