title: Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway.
abstract: 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.
authors.affiliation: 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.
authors.forename: Shutong
authors.initials: S
authors.lastname: Yao
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, Taishan Medical University, Taian, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.affiliation: Affiliated Hospital, Chengde Medical University, Chengde, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: College of Basic Medical Sciences, Taishan Medical University, Taian, China.
authors.forename: Jinguo
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Central Hospital of Taian, Taian, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, Central Hospital of Taian, Taian, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yue
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, Taishan Medical University, Taian, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, Taishan Medical University, Taian, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Jiao
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, Taishan Medical University, Taian, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Yang
authors.affiliation: Affiliated Hospital, Chengde Medical University, Chengde, China.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Basic Medical Sciences, Taishan Medical University, Taian, China.
authors.forename: Xiangjian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, Taishan Medical University, Taian, China shucunqin@hotmail.com.
authors.forename: Shucun
authors.initials: S
authors.lastname: Qin
mesh_terms: D017209:Apoptosis / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D009861:Onium Compounds / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; C497249:DDIT3 protein, human; D008075:Lipoproteins, HDL; D009861:Onium Compounds; D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051742:Transcription Factor CHOP; C007517:diphenyleneiodonium
keywords: CCAAT-enhancer-binding protein homologous protein; atherosclerosis; endoplasmic reticulum stress; oxidative stress