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首页> 外文期刊>Molecular and Cellular Biology >NAD(P)H Oxidase Nox-4 Mediates 7-Ketocholesterol-Induced Endoplasmic Reticulum Stress and Apoptosis in Human Aortic Smooth Muscle Cells
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NAD(P)H Oxidase Nox-4 Mediates 7-Ketocholesterol-Induced Endoplasmic Reticulum Stress and Apoptosis in Human Aortic Smooth Muscle Cells

机译：NAD（P）H氧化酶Nox-4介导7-胆固醇诱导的人主动脉平滑肌细胞内质网应激和凋亡

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The mechanisms involved in the cytotoxic action of oxysterols in the pathogenesis of atherosclerosis still remain poorly understood. Among the major oxysterols present in oxidized low-density lipoprotein, we show here that 7-ketocholesterol (7-Kchol) induces oxidative stress and/or apoptotic events in human aortic smooth muscle cells (SMCs). This specific effect of 7-Kchol is mediated by a robust upregulation (threefold from the basal level) of Nox-4, a reactive oxygen species (ROS)-generating NAD(P)H oxidase homologue. This effect was highlighted by silencing Nox-4 expression with a specific small interfering RNA, which significantly reduced the 7-Kchol-induced production of ROS and abolished apoptotic events. Furthermore, the 7-Kchol activating pathway included an early triggering of endoplasmic reticulum stress, as assessed by transient intracellular Ca2+ oscillations, and the induction of the expression of the cell death effector CHOP and of GRP78/Bip chaperone via the activation of IRE-1, all hallmarks of the unfolded protein response (UPR). We also showed that 7-Kchol activated the IRE-1/Jun-NH2-terminal kinase (JNK)/AP-1 signaling pathway to promote Nox-4 expression. Silencing of IRE-1 and JNK inhibition downregulated Nox-4 expression and subsequently prevented the UPR-dependent cell death induced by 7-Kchol. These findings demonstrate that Nox-4 plays a key role in 7-Kchol-induced SMC death, which is consistent with the hypothesis that Nox-4/oxysterols are involved in the pathogenesis of atherosclerosis.
机译：在动脉粥样硬化的发病机理中，与氧固醇的细胞毒性作用有关的机制仍然知之甚少。在氧化的低密度脂蛋白中存在的主要氧固醇中，我们在这里显示7-酮胆固醇（7-Kchol）在人主动脉平滑肌细胞（SMCs）中诱导氧化应激和/或凋亡事件。 7-Kchol的这种特殊作用是由Nox-4（一种产生活性氧（ROS）的NAD（P）H氧化酶同源物）的强烈上调（从基础水平提高三倍）介导的。通过用特定的小分子干扰RNA沉默Nox-4表达，可以显着提高这种效果，从而显着降低7-Kchol诱导的ROS产生并消除凋亡事件。此外，通过瞬时细胞内Ca 2 + 振荡评估，7-Kchol激活途径包括内质网应激的早期触发，以及诱导细胞死亡效应因子CHOP和GRP78 /的表达。通过IRE-1的激活来刺激伴侣，这是未折叠蛋白反应（UPR）的所有标志。我们还表明7-Kchol激活IRE-1 / Jun-NH 2 末端激酶（JNK）/ AP-1信号通路来促进Nox-4表达。 IRE-1和JNK抑制的沉默下调了Nox-4的表达，并随后阻止了7-Kchol诱导的UPR依赖性细胞死亡。这些发现表明，Nox-4在7-Kchol诱导的SMC死亡中起关键作用，这与Nox-4 /氧固醇参与动脉粥样硬化的发病机理的假设相一致。

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