Abstract
This study was designed to explore the inductive effect of glycated high‐density lipoprotein (gly‐HDL) on endoplasmic reticulum (ER) stress‐C/EBP homologous protein (CHOP)‐mediated macrophage apoptosis and its relationship with autophagy. Our results showed that gly‐HDL caused macrophage apoptosis with concomitant activation of ER stress pathway, including nuclear translocation of activating transcription factor 6, phosphorylation of protein kinase‐like ER kinase (PERK) and eukaryotic translation initiation factor 2α, and CHOP up‐regulation, which were inhibited by 4‐phenylbutyric acid (PBA, an ER stress inhibitor) and the gene silencing of PERK and CHOP. Similar data were obtained from macrophages treated by HDL isolated from diabetic patients. Gly‐HDL induced macrophage autophagy as assessed by up‐regulation of beclin‐1, autophagy‐related gene 5 and microtubule‐associated protein one light chain 3‐II, which were depressed by PBA and PERK siRNA. Gly‐HDL‐induced apoptosis, PERK phosphorylation and CHOP up‐regulation were suppressed by rapamycin (an autophagy inducer), whereas aggravated by 3‐methyladenine (an autophagy inhibitor) and beclin‐1 siRNA. Administration of diabetic apoE−/− mice with rapamycin attenuated MOMA‐2 and CHOP up‐regulation and apoptosis in atherosclerotic lesions. These data indicate that gly‐HDL may induce macrophage apoptosis through activating ER stress‐CHOP pathway and ER stress mediates gly‐HDL‐induced autophagy, which in turn protects macrophages against apoptosis by alleviating CHOP pathway.
Highlights
Exacerbated atherosclerosis is the most common and serious com‐ plication in patients with diabetes mellitus (DM), which is closely associated with hyperglycaemia and dyslipoproteinaemia, al‐ though the pathogenic mechanisms are incompletely elucidated
Macrophage apoptosis is a key event in the formation and rupture of atherosclerotic plaques and accelerated atherosclerosis is the major complication of DM, a metabolic disease affecting people worldwide
The present study was the first to report that glycated high‐density lipoprotein (HDL) (gly‐HDL) elicited macrophage apoptosis by activating the endoplasmic reticulum (ER) stress‐ C/EBP homologous protein (CHOP) pathway and the up‐regulation of autophagy was a cellular protective response that attenuated ER stress‐CHOP‐mediated mac‐ rophage apoptosis induced by gly‐HDL, which was supported by the following findings
Summary
Exacerbated atherosclerosis is the most common and serious com‐ plication in patients with diabetes mellitus (DM), which is closely associated with hyperglycaemia and dyslipoproteinaemia, al‐ though the pathogenic mechanisms are incompletely elucidated. High‐glucose, free fatty acids and inflammatory challenge stimulate the ER stress‐CHOP pathway and oxidative stress in β cells.[8] CHOP deletion protects β cells against dysfunc‐ tion and apoptosis in diet‐ and genetic‐induced diabetes models in mice.[9] Macrophage apoptosis plays a key role in each stage of ath‐ erosclerosis, especially in the destabilization and rupture of ath‐ erosclerotic plaques, which may contribute to the majority of acute cardiovascular disease events.[10] Accumulating evidence has shown that ER stress‐CHOP pathway‐mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques.[11,12] Previous studies including our own have demonstrated that ox‐LDL can initiate macrophage and endothelial cell apoptosis by elevating the CHOP pathway.[13,14,15] our recent study has shown that CHOP mediates oxidized HDL‐induced macrophage apopto‐ sis.[16] we hypothesized that gly‐HDL may cause macrophage apoptosis by activating ER stress‐CHOP signals. We investigated the roles of ER stress and autophagy in gly‐HDL‐in‐ duced macrophage apoptosis and the crosstalk between them in atherosclerosis
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