7‐Ketocholesterol‐induced apoptosis
7‐Ketocholesterol‐induced apoptosis
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7-酮胆固醇诱导的细胞凋亡
DOI：
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
D. Néel
中科院分区：
文献类型：
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作者：
Arnaud Berthier;S. Lemaire‐Ewing;C. Prunet;T. Montange;A. Vejux;J. Pais de Barros;S. Monier;P. Gambert;G. Lizard;D. Néel
氧固醇，特别是7-酮胆固醇，似乎与动脉粥样硬化的病理生理学密切相关。怀疑这些分子对血管壁细胞和单核细胞/巨噬细胞具有细胞毒性，特别是通过诱导细胞凋亡。先前的研究已经证明，7-酮基胆固醇诱导的细胞凋亡是由胞质游离Ca 2+的持续增加触发的，这通过激活钙依赖性磷酸酶钙调磷酸酶来激活细胞凋亡的线粒体途径，导致“仅BH 3”蛋白BAD的去磷酸化。然而，对结果的全面研究表明，其他途径与7-酮基胆固醇诱导的细胞毒性有关。在这项研究中，我们证明了在7-酮胆固醇诱导的细胞凋亡过程中，另外两种钙依赖性途径的参与。通过钙依赖性酪氨酸激酶PYK 2激活MEK→ERK途径，如通过使用MEK抑制剂U 0126所示的延迟凋亡的存活途径，以及涉及另一种促凋亡BH 3蛋白Bim的途径。 事实上，人单核细胞THP-1细胞的7-酮胆固醇处理诱导Bim-LC 8从微管相关动力蛋白运动复合体中释放，并与Bcl-2相关。因此，7-酮基胆固醇诱导的细胞凋亡似乎是一种复杂的现象，由几种促细胞凋亡途径和一种存活途径的钙依赖性激活引起。
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.
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影响因子：
6.5
作者：
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通讯作者：
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影响因子：
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通讯作者：
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
16
作者：
Puthalakath, H;Huang, DCS;Strasser, A
通讯作者：
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影响因子：
6.5
作者：
Colles,SM;Irwin,KC;Chisolm,GM
通讯作者：
Chisolm,GM