Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Shutong Yao,Hua Tian,Li Zhao,Jinguo Li,Libo Yang,Feng Yue,Yanyan Li,Peng Jiao,Nana Yang,Yiwei Wang,Xiangjian Zhang,Shucun Qin

doi:10.1194/jlr.m071142

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.

Highlights

Oxidized HDL, unlike native HDL that exerts antiatherogenic effects, plays a proatherogenic role
We found that Oxidized HDL (ox-HDL) prepared in vitro and HDL isolated from patients with metabolic syndrome (MS) activated the endoplasmic reticulum (ER) stress-CHOPmediated apoptotic pathway in macrophages, which could be blocked by oxidative stress inhibitors, toll-like receptor 4 (TLR4)-specific small interfering RNA, and TLR4 antibody
Because the ER stress-CCAAT-enhancerbinding protein homologous protein (CHOP) pathway plays an important role in macrophage apoptosis [15,16,17], we explored the effect of ox-HDL on CHOP and its two important upstream molecules, activating transcription factor 6 (ATF6) and PERK

Summary

Introduction

Oxidized HDL (ox-HDL), unlike native HDL that exerts antiatherogenic effects, plays a proatherogenic role. 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. 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.— Yao, S., H. (ox-HDL) loses the antiatherogenic functions of native HDL [5,6,7] and exerts effects instead by inducing proliferation and migration of vascular smooth muscle cells [8], promoting platelet activation [9], and causing apoptosis in endothelial cells [10].

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