Endoplasmic reticulum stress‐dependent autophagy inhibits glycated high‐density lipoprotein‐induced macrophage apoptosis by inhibiting CHOP pathway

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 si RNA . 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 si RNA . 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.

Erythropoietin Derived Peptide Improved Endoplasmic Reticulum Stress and Ischemia-Reperfusion Related Cellular and Renal Injury

“…Moreover, the number of early apoptotic cells was also reduced by CHOP siRNA compared to the H 2 O 2 and NC siRNA groups, and the cell survival was improved. These data were consistent to the CHOP −/− knockout model in vivo (21,43,44). Furthermore, the correlation analysis revealed that CHOP mRNA was positively correlated with PERK, 17 kD active caspase-3 and HMGB-1, and apoptosis, but negatively related to cell viability.…”

“…UPR could gradually develop into apoptosis and further induces inflammation, if ERS is too severe to overcome. CCAAT/enhancer-binding protein homologous protein (CHOP) is an ERS-induced transcriptional regulator and key to ERSmediated apoptotic pathway (20,21). The over expression of CHOP plays an important role in the activation of C-Jun Nterminal kinase (JNK) that contributes to apoptotic cell death (22,23).…”

Endoplasmic Reticulum Stress: A Critical Molecular Driver of Endothelial Dysfunction and Cardiovascular Disturbances Associated with Diabetes

“…These effects were prevented by the chemical chaperone, TUDCA, and the silencing of CHOP [68]. Very recently Tian et al [69] reported that glycated high-density lipoprotein (HDL) also contributes to atherogenesis via the activation of the ER stress response. Authors exposed RAW264.7 macrophages to glycated HDL, prepared from native HDL collected from healthy donors and then incubated with high glucose.…”

“…Similar findings were replicated using glycated HDL collected from diabetic patients. A focal role for autophagy in the effects mediated by glycated HDL was highlighted both in vitro and in vivo using an ApoE −/− mouse model of atherosclerosis and an inhibitor of autophagy [69]. Work by Li et al [70] has shed light on the role of apolipoprotein C3 (ApoC3), which is found in lipoproteins rich in triglycerides, in atherosclerosis.…”

Activation of PERK Contributes to Apoptosis and G2/M Arrest by Microtubule Disruptors in Human Colorectal Carcinoma Cells

“…Protein kinase RNA (PKR)-like endoplasmic reticular (ER) kinase (PERK), a type of ER stress sensor, is a serine/threonine kinase that regulates the survival and death of cells [22]. Activation of PERK leading to induction of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation was considered to be cytoprotective [23]; however, several previous studies indicated that phosphorylation of eIF2α was able to increase activating transcription factor 4 (ATF4) protein expression to initiate proapoptotic signaling [24,25]. Our previous studies demonstrated that the natural chemical evodiamine (EVO) effectively induced apoptosis and G 2 /M arrest with increased PERK protein phosphorylation in various cancer cells, including human ovarian cancer cells, glioblastoma cells, and renal cell carcinoma cells [26,27].…”