Peroxynitrite causes endoplasmic reticulum stress and apoptosis in human vascular endothelium -: Implications in atherogenesis
Peroxynitrite causes endoplasmic reticulum stress and apoptosis in human vascular endothelium -: Implications in atherogenesis
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DOI：
10.1161/01.atv.0000189159.96900.d9
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发表时间：
2005-12-01
影响因子：
8.7
通讯作者：
Austin, RC
中科院分区：
文献类型：
--
作者：
Dickhout, JG;Hossain, GS;Austin, RC
目的-过氧亚硝酸盐，一种由NO与超氧化物反应产生的强氧化剂，与动脉粥样硬化的促进有关。我们设计了这项研究，以确定是否过氧亚硝酸盐诱导其proatherogenic通过诱导内质网（ER）stress.Methods和结果-人血管内皮细胞与Sin-1，过氧亚硝酸盐发电机，诱导表达的ER伴侣GRP 78和GRP 94和增加eIF 2 α磷酸化。这些影响被过氧亚硝酸根清除剂尿酸抑制。Sin-1引起ER-Ca 2+耗竭，这是一种已知诱导ER应激的效应，导致胞质Ca 2+升高和程序性细胞死亡（PCD）。还发现Sin-1处理通过3-硝基酪氨酸和GRP 78共定位直接作用于ER。腺病毒介导的GRP 78在内皮细胞中的过表达阻止了Sin-1诱导的PCD。与这些在体外的研究结果一致，3-硝基酪氨酸观察和共定位与GRP 78在内皮细胞的早期动脉粥样硬化病变的载脂蛋白E -缺陷mice.Conclusions -过氧亚硝酸盐是一种ER应激诱导剂。其作用包括ER-Ca 2+耗竭，这是ER应激诱导的一种已知机制。观察到含3-硝基酪氨酸的蛋白质与早期动脉粥样硬化病变内的ER应激标志物共定位，表明过氧亚硝酸盐通过涉及ER应激的机制促进动脉粥样硬化形成。
Objective - Peroxynitrite, a potent oxidant generated by the reaction of NO with superoxide, has been implicated in the promotion of atherosclerosis. We designed this study to determine whether peroxynitrite induces its proatherogenic effects through induction of endoplasmic reticulum ( ER) stress.Methods and Results - Human vascular endothelial cells treated with Sin-1, a peroxynitrite generator, induced the expression of the ER chaperones GRP78 and GRP94 and increased eIF2 alpha phosphorylation. These effects were inhibited by the peroxynitrite scavenger uric acid. Sin-1 caused the depletion of ER-Ca2+, an effect known to induce ER stress, resulting in the elevation of cytosolic Ca2+ and programmed cell death (PCD). Sin-1 treatment was also found, via 3-nitrotyrosine and GRP78 colocalization, to act directly on the ER. Adenoviral-mediated overexpression of GRP78 in endothelial cells prevented Sin-1 - induced PCD. Consistent with these in vitro findings, 3-nitrotyrosine was observed and colocalized with GRP78 in endothelial cells of early atherosclerotic lesions from apolipoprotein E - deficient mice.Conclusions - Peroxynitrite is an ER stress-inducing agent. Its effects include the depletion of ER-Ca2+, a known mechanism of ER stress induction. The observation that 3-nitrotyrosine - containing proteins colocalize with markers of ER stress within early atherosclerotic lesions suggests that peroxynitrite contributes to atherogenesis through a mechanism involving ER stress.