Yung Hong-wa, Korolchuk Svitlana, Tolkovsky Aviva M, Charnock-Jones D Stephen, Burton Graham J
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
FASEB J. 2007 Mar;21(3):872-84. doi: 10.1096/fj.06-6054com. Epub 2006 Dec 13.
Oxidative stress is central to ischemia-reperfusion injury. The role of the endoplasmic reticulum (ER) in this process is uncertain. In ER signaling, PERK-Nrf2 and Ire-CHOP are two pathways that determine cell fate under stress. PERK-Nrf2 up-regulates antioxidant enzyme expression whereas Ire-CHOP promotes apoptosis. We have identified a novel pathway in ER stress-induced apoptosis after ischemia-reperfusion in vitro involving translational suppression of the survival kinase PKB/Akt (Akt), and elucidated an alternative protective role of antioxidants in the regulation of Akt activity. Using human choriocarcinoma JEG-3 cells, we found that sustained activation of ER stress by tunicamycin or thapsigargin exacerbated apoptosis in oxygen-glucose-deprived cells during reoxygenation. This was mediated via a reduction in phosphorylated Akt secondary to down-regulation of protein translation rather than suppression of phosphorylation. Transient overexpression of wild-type Akt, but not kinase-dead Akt, in JEG-3 cells diminished tunicamycin-OGD reoxygenation-induced apoptosis. The antioxidants Trolox and Edaravone reduced apoptosis, but the protective effect of Trolox was abrogated by the PI3K inhibitor, LY294002. We speculate that sustained ER stress may contribute to the placental dysfunction seen in human pregnancy complications.
氧化应激是缺血再灌注损伤的核心。内质网（ER）在此过程中的作用尚不确定。在ER信号传导中，PERK-Nrf2和Ire-CHOP是在应激状态下决定细胞命运的两条途径。PERK-Nrf2上调抗氧化酶表达，而Ire-CHOP促进细胞凋亡。我们在体外缺血再灌注后的ER应激诱导凋亡中发现了一条新途径，涉及存活激酶PKB/Akt（Akt）的翻译抑制，并阐明了抗氧化剂在调节Akt活性中的另一种保护作用。使用人绒毛膜癌JEG-3细胞，我们发现衣霉素或毒胡萝卜素持续激活ER应激会加剧复氧期间氧葡萄糖剥夺细胞的凋亡。这是通过蛋白质翻译下调继发的磷酸化Akt减少介导的，而不是通过抑制磷酸化。在JEG-3细胞中瞬时过表达野生型Akt而非激酶失活的Akt可减少衣霉素-氧葡萄糖剥夺复氧诱导的凋亡。抗氧化剂曲克芦丁和依达拉奉可减少细胞凋亡，但曲克芦丁的保护作用被PI3K抑制剂LY294002消除。我们推测持续的ER应激可能导致人类妊娠并发症中出现的胎盘功能障碍。
