Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha 410078, China.
Biochem Biophys Res Commun. 2013 Sep 6;438(4):732-8. doi: 10.1016/j.bbrc.2013.07.098. Epub 2013 Jul 31.
The high mobility group 1B protein (HMGB1) mediates chronic inflammatory responses in endothelial cells, which play a critical role in atherosclerosis. However, the underlying mechanism is unknown. The goal of our study was to identify the effects of HMGB1 on the RAGE-induced inflammatory response in endothelial cells and test the possible involvement of the endoplasmic reticulum stress pathway. Our results showed that incubation of endothelial cells with HMGB1 (0.01-1 μg/ml) for 24h induced a dose-dependent activation of endoplasmic reticulum stress transducers, as assessed by PERK and IRE1 protein expression. Moreover, HMGB1 also promoted nuclear translocation of ATF6. HMGB1-mediated ICAM-1 and P-selectin production was dramatically suppressed by PERK siRNA or IRE1 siRNA. However, non-targeting siRNA had no such effects. HMGB1-induced increases in ICAM-1 and P-selectin expression were also inhibited by a specific eIF2α inhibitor (salubrinal) and a specific JNK inhibitor (SP600125). Importantly, a blocking antibody specifically targeted against RAGE (anti-RAGE antibody) decreased ICAM-1, P-selectin and endoplasmic reticulum stress molecule (PERK, eIF2α, IRE1 and JNK) protein expression levels. Collectively, these novel findings suggest that HMGB1 promotes an inflammatory response by inducing the expression of ICAM-1 and P-selectin via RAGE-mediated stimulation of the endoplasmic reticulum stress pathway.
高迁移率族蛋白 1B（HMGB1）在动脉粥样硬化中起关键作用，介导内皮细胞的慢性炎症反应。然而，其潜在机制尚不清楚。本研究旨在探讨 HMGB1 对内皮细胞 RAGE 诱导的炎症反应的影响，并检验内质网应激途径的可能参与。我们的结果表明，HMGB1（0.01-1μg/ml）孵育内皮细胞 24h 后，通过 PERK 和 IRE1 蛋白表达评估，内质网应激转导物呈剂量依赖性激活。此外，HMGB1 还促进了 ATF6 的核易位。PERK siRNA 或 IRE1 siRNA 显著抑制了 HMGB1 介导的 ICAM-1 和 P-选择素的产生。而非靶向 siRNA 则无此作用。HMGB1 诱导的 ICAM-1 和 P-选择素表达增加也被特定的 eIF2α 抑制剂（salubrinal）和特定的 JNK 抑制剂（SP600125）抑制。重要的是，针对 RAGE 的阻断抗体（抗-RAGE 抗体）降低了 ICAM-1、P-选择素和内质网应激分子（PERK、eIF2α、IRE1 和 JNK）的蛋白表达水平。综上所述，这些新发现表明，HMGB1 通过 RAGE 介导的内质网应激途径的刺激，促进 ICAM-1 和 P-选择素的表达，从而促进炎症反应。
