HDLs inhibit endoplasmic reticulum stress and autophagic response induced by oxidized LDLs
HDLs inhibit endoplasmic reticulum stress and autophagic response induced by oxidized LDLs
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DOI：
10.1038/cdd.2010.149
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发表时间：
2011-05-01
影响因子：
12.4
通讯作者：
Vindis, C.
中科院分区：
文献类型：
--
作者：
Muller, C.;Salvayre, R.;Vindis, C.
氧化型低密度脂蛋白(OxLDL)的细胞凋亡作用是通过一系列复杂的信号事件来实现的，这些信号事件涉及细胞内钙稳态的破坏。OxLDLS还通过激活IRE1α/c-jun N末端激酶通路，触发内质网应激，从而可能导致细胞功能障碍和细胞凋亡。此外，内质网应激和氧化脂质已被证明可触发自噬。抗动脉粥样硬化的高密度脂蛋白(HDL)对oxLDLS的毒性具有保护作用。为了更深入地研究高密度脂蛋白的保护作用机制，我们研究了内质网应激和自噬是否与oxLDLS诱导的细胞凋亡有关，以及高密度脂蛋白是否阻止了这些应激过程。我们报道，在人内皮细胞中，高密度脂蛋白阻止oxLDL诱导的内质网应激传感器IRE1α、eIF2α和ATF6的激活以及随后促凋亡介质JNK和CHOP的激活。OxLDL还触发自噬的激活，通过LC3处理和Beclin-1表达来评估。自噬过程不依赖于内质网应激的促凋亡臂，但Beclin-1有助于PS暴露和随后的oxLDLS暴露细胞的吞噬。高密度脂蛋白可防止oxLDLS诱导自噬和PS暴露。最后，oxLDLS引发的胞内钙离子去调节是一个共同的信号通路，介导了内质网应激诱导的细胞死亡和自噬，所有这些事件都被HDLS阻断。《细胞死亡与分化》(2011年)18817828；doi：10.1038/cdd.2010.149；2010年11月26日在线发布
The apoptotic effect of oxidized LDLs (oxLDLs) is mediated through a complex sequence of signaling events involving a deregulation of the cytosolic Ca2+ homeostasis. OxLDLs also trigger ER stress that may lead to cellular dysfunction and apoptosis, through the activation of the IRE1 alpha/c-Jun N-terminal kinase pathway. Moreover, ER stress and oxidized lipids have been shown to trigger autophagy. The antiatherogenic high-density lipoproteins (HDLs) display protective effects against oxLDLs toxicity. To more deeply investigate the mechanisms mediating the protective effects of HDLs, we examined whether ER stress and autophagy were implicated in oxLDLs-induced apoptosis and whether HDLs prevented these stress processes. We report that, in human endothelial cells, HDLs prevent the oxLDL-induced activation of the ER stress sensors IRE1 alpha, eIF2 alpha and ATF6 and subsequent activation of the proapoptotic mediators JNK and CHOP. OxLDLs also trigger the activation of autophagy, as assessed by LC3 processing and Beclin-1 expression. The autophagic process is independent of the proapoptotic arms of ER stress, but Beclin-1 contributes to PS exposure and subsequent phagocytosis of oxLDLs exposed cells. Induction of autophagy and PS exposure by oxLDLs is prevented by HDLs. Finally, the cytosolic Ca2+ deregulation triggered by oxLDLs is a common signaling pathway that mediates ER stress-induced cell death and autophagy, all these events being blocked by HDLs. Cell Death and Differentiation (2011) 18, 817-828; doi:10.1038/cdd.2010.149; published online 26 November 2010