T-cadherin attenuates the PERK branch of the unfolded protein response and protects vascular endothelial cells from endoplasmic reticulum stress-induced apoptosis
T-cadherin attenuates the PERK branch of the unfolded protein response and protects vascular endothelial cells from endoplasmic reticulum stress-induced apoptosis
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DOI：
10.1016/j.cellsig.2010.04.008
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发表时间：
2010-09-01
影响因子：
4.8
通讯作者：
Resink, Therese J.
中科院分区：
文献类型：
--
作者：
Kyriakakis, Emmanouil;Philippova, Maria;Resink, Therese J.
内质网（ER）应激激活的扰动，在ER稳态诱导未折叠蛋白反应（UPR）与伴侣Grp 78作为关键激活剂的UPR信号。UPR的目的是恢复正常的ER功能：然而，长期或严重的ER应激会触发受损细胞的凋亡，以确保整个生物体的保护。最近的研究结果支持ER应激诱导的血管细胞凋亡与心血管病变的关联。钙粘蛋白（T-cad），钙粘蛋白超家族的非典型糖基磷脂酰肌醇锚定成员，在动脉粥样硬化病变中上调。在这里，我们调查的能力T-cad影响UPR信号和内皮细胞（EC）的生存在ER应激。用多种ER应激诱导化合物（毒胡萝卜素、二硫苏糖醇、布雷菲德菌素A）处理EC。衣霉素A23187或同型半胱氨酸）和通过UPR信号分子Grp 78（78 kDa的葡萄糖调节蛋白）、磷酸化eIF 2 α（磷酸化真核起始因子2 α）和CHOP（C/EBP同源蛋白）水平的增加验证的ER应激的诱导。所有化合物还增加T-cad mRNA和蛋白水平。EC中T-cad的过表达或沉默分别减弱或放大了ER应激诱导的磷酸化eIF 2 α，Grp 78的增加。CHOP和活性半胱天冬酶。T-cad过表达或T-cad沉默对EC中ER应激反应的影响不受N-乙酰半胱氨酸（活性氧清除剂），LY 294002（磷脂酰肌醇-3-激酶抑制剂）或SP 6000125（Jun N-末端激酶抑制剂）的影响。这些数据表明，在ER应激过程中EC上T-cad的上调减弱了UPR级联的促凋亡PERK（PKR（双链RNA活化蛋白激酶）样ER激酶）分支的激活，从而保护EC免受ER应激诱导的凋亡。(C)2010年爱思唯尔公司All rights reserved.
Endoplasmic reticulum (ER) stress activated by perturbations in ER homeostasis induces the unfolded protein response (UPR) with chaperon Grp78 as the key activator of UPR signalling. The aim of UPR is to restore normal ER function: however prolonged or severe ER stress triggers apoptosis of damaged cells to ensure protection of the whole organism. Recent findings support an association of ER stress-induced apoptosis of vascular cells with cardiovascular pathologies. T-cadherin (T-cad), an atypical glycosylphosphatidylinositol-anchored member of the cadherin superfamily is upregulated in atherosclerotic lesions. Here we investigate the ability of T-cad to influence UPR signalling and endothelial cell (EC) survival during ER stress. EC were treated with a variety of ER stress-inducing compounds (thapsigargin, dithiothereitol, brefeldin A. tunicamycin. A23187 or homocysteine) and induction of ER stress validated by increases in levels of UPR signalling molecules Grp78 (glucose-regulated protein of 78 kDa), phospho-eIF2 alpha (phosphorylated eukaryotic initiation factor 2 alpha) and CHOP (C/EBP homologous protein). All compounds also increased T-cad mRNA and protein levels. Overexpression or silencing of T-cad in EC respectively attenuated or amplified the ER stress-induced increase in phospho-eIF2 alpha, Grp78. CHOP and active caspases. Effects of T-cad-overexpression or T-cad-silencing on ER stress responses in EC were not affected by inclusion of either N-acetylcysteine (reactive oxygen species scavenger), LY294002 (phosphatidylinositol-3-kinase inhibitor) or SP6000125 (Jun N-terminal kinase inhibitor). The data suggest that upregulation of T-cad on EC during ER stress attenuates the activation of the proapoptotic PERK (PKR (double-stranded RNA-activated protein kinase)-like ER kinase) branch of the UPR cascade and thereby protects EC from ER stress-induced apoptosis. (C) 2010 Elsevier Inc. All rights reserved.