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

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.

• Authors: Arnaud Berthier, Stéphanie Lemaire-Ewing, Céline Prunet, Thomas Montange, Anne Vejux, Jean Paul Pais de Barros, Serge Monier, Philippe Gambert, Gérard Lizard, Dominique Néel
• Journal: The FEBS journal (FEBS J) Vol. 272 Issue 12 Pg. 3093-104 (Jun 2005) ISSN: 1742-464X [Print] England
• PMID: 15955068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BAD protein, human
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Carrier Proteins
• Enzyme Inhibitors
• Ketocholesterols
• Membrane Proteins
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• bcl-Associated Death Protein
• MAP2K2 protein, human
• DDR1 protein, human
• Discoidin Domain Receptor 1
• Protein-Tyrosine Kinases
• Receptor Protein-Tyrosine Kinases
• Focal Adhesion Kinase 2
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• Dyneins
• 7-ketocholesterol
• Calcium

Topics

• Apoptosis (drug effects, physiology)
• Apoptosis Regulatory Proteins
• Bcl-2-Like Protein 11
• Calcium (metabolism)
• Carrier Proteins (drug effects, metabolism)
• Cells, Cultured
• Discoidin Domain Receptor 1
• Dyneins (drug effects, metabolism)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Focal Adhesion Kinase 2
• Humans
• Ketocholesterols (metabolism, pharmacology)
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 2 (antagonists & inhibitors, metabolism)
• Membrane Proteins (drug effects, 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, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (drug effects, metabolism)
• Receptor Protein-Tyrosine Kinases (metabolism)
• Signal Transduction
• bcl-Associated Death Protein