Endoplasmic reticulum stress plays a role in the advanced glycation end product-induced inflammatory response in endothelial cells |
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Authors: | Lili Wu Da WangYan Xiao Xiaoyan ZhouLiqun Wang Bo ChenQiang Li Xiaohua GuoQiaobing Huang |
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Affiliation: | Department of Pathophysiology, Key Lab for Shock and Microcirculation Research, Southern Medical University, Guangzhou 510515, P. R. China |
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Abstract: | AimsBoth advanced glycation end products (AGEs) and endoplasmic reticulum (ER) stress play important roles in the development of various diseases. This study aimed to clarify the consequence of AGE-induced ER stress and its underlying mechanisms in human umbilical venous endothelial cells (HUVECs).Main methodsAGE-induced ER stress was assessed by the increased expression and activation of the ER stress marker proteins GRP78, IRE1α and JNK, which were detected using Western blot. NF-κB translocation was revealed using Western blot and immunofluorescent staining in IRE1α-knockdown HUVECs. The mechanism of AGE-induced ER stress was also explored by inhibiting the effect of reactive oxygen species (ROS) using NADPH oxidase 4 (Nox4) siRNA and the antioxidant reduced glutathione (GSH). The cellular ROS level was measured using flow cytometry.Key findingsAGEs time- and dose-dependently enhanced the expression of GRP78 and increased the phosphorylation of IRE1α and its downstream signal JNK in HUVECs. siRNA-induced IRE1α down-regulation suppressed AGE-induced NF-κB p65 nuclear translocation. Inhibiting the ROS production using Nox4 siRNA or antagonizing ROS using GSH reduced cellular ROS level and attenuated AGE-induced GRP78 expression and IRE1α and JNK activation.SignificanceThis study confirms that AGE-induced ER stress in HUVECs focuses on the ER stress-enhanced inflammatory response through JNK and NF-κB activation. It further reveals the involvement of ROS in the AGE-induced ER stress mechanism. |
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Keywords: | Advanced glycation end products Endoplasmic reticulum stress c-Jun N-terminal kinase Nuclear factor -κB Reactive oxygen species |
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