Yao Shutong, Tian Hua, Zhao Li, Li Jinguo, Yang Libo, Yue Feng, Li Yanyan, Jiao Peng, Yang Nana, Wang Yiwei, Zhang Xiangjian, Qin Shucun
Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, Taishan Medical University, Taian, China.
College of Basic Medical Sciences, Taishan Medical University, Taian, China.
J Lipid Res. 2017 Jan;58(1):164-177. doi: 10.1194/jlr.M071142. Epub 2016 Nov 28.
Oxidized HDL (ox-HDL), unlike native HDL that exerts antiatherogenic effects, plays a proatherogenic role. However, the underlying mechanisms are not completely understood. This study was designed to explore the inductive effect of ox-HDL on endoplasmic reticulum (ER) stress-CCAAT-enhancer-binding protein homologous protein (CHOP)-mediated macrophage apoptosis and its upstream mechanisms. Our results showed that ox-HDL could be ingested by macrophages, causing intracellular lipid accumulation. As with tunicamycin (an ER stress inducer), ox-HDL induced macrophage apoptosis with concomitant activation of ER stress pathway, including nuclear translocation of activating transcription factor 6, phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α, and upregulation of glucose-regulated protein 78 and CHOP, which were inhibited by 4-phenylbutyric acid (PBA, an ER stress inhibitor) and CHOP gene silencing. Additionally, diphenyleneiodonium (DPI, an oxidative stress inhibitor), probucol (a reactive oxygen species scavenger), and toll-like receptor 4 (TLR4) silencing reduced ox-HDL-induced macrophage apoptosis, oxidative stress, and CHOP upregulation. Moreover, HDL isolated from patients with metabolic syndrome induced macrophage apoptosis, oxidative stress, and CHOP upregulation, which were blocked by PBA and DPI. These data indicate that ox-HDL may activate ER stress-CHOP-induced apoptotic pathway in macrophages via enhanced oxidative stress and that this pathway may be mediated by TLR4.
与具有抗动脉粥样硬化作用的天然高密度脂蛋白（HDL）不同，氧化型高密度脂蛋白（ox-HDL）具有促动脉粥样硬化作用。然而，其潜在机制尚未完全明确。本研究旨在探讨ox-HDL对内质网（ER）应激-CCAAT增强子结合蛋白同源蛋白（CHOP）介导的巨噬细胞凋亡的诱导作用及其上游机制。我们的结果显示，ox-HDL可被巨噬细胞摄取，导致细胞内脂质蓄积。与衣霉素（一种ER应激诱导剂）一样，ox-HDL诱导巨噬细胞凋亡，同时激活ER应激途径，包括激活转录因子6的核转位、蛋白激酶样ER激酶和真核翻译起始因子2α的磷酸化，以及葡萄糖调节蛋白78和CHOP的上调，而4-苯基丁酸（PBA，一种ER应激抑制剂）和CHOP基因沉默可抑制这些变化。此外，二苯基碘鎓（DPI，一种氧化应激抑制剂）、普罗布考（一种活性氧清除剂）和Toll样受体4（TLR4）沉默可减少ox-HDL诱导的巨噬细胞凋亡、氧化应激和CHOP上调。此外，从代谢综合征患者中分离出的HDL诱导巨噬细胞凋亡、氧化应激和CHOP上调，而PBA和DPI可阻断这些变化。这些数据表明，ox-HDL可能通过增强氧化应激激活巨噬细胞中ER应激-CHOP诱导的凋亡途径，且该途径可能由TLR4介导。
