7‐Ketocholesterol‐induced apoptosis

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 Ca 2+ , 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.