School of Pharmacy, Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, USA.
J Cardiovasc Pharmacol. 2010 Jan;55(1):49-55. doi: 10.1097/FJC.0b013e3181c37d86.
BACKGROUND/AIM: Recent evidence suggests that endoplasmic reticulum (ER) stress provoked under diabetic conditions augments the expression of scavenger receptors on macrophages, promoting the uptake of oxidized low-density lipoprotein uptake and atherogenesis. The aim of the present study was to test the hypothesis that the chemical chaperone tauroursodeoxycholic acid (TUDCA) attenuates lipid accumulation in macrophages subjected to ER stress.
Cultured human macrophages were subjected to ER stress by treating them with tunicamycin. Lipid uptake by macrophages subjected to ER stress in the presence or absence of TUDCA was assessed by oil red O staining and by assessing the cellular uptake of Dil-oxidized low-density lipoprotein by fluorescence measurement. Protein levels and phosphorylation status of ER stress markers, insulin-signaling molecules, and scavenger receptor were assessed by Western blotting.
Treatment of cultured human macrophages with the ER stressor tunicamycin caused an increase in the protein levels of cluster of differentiation 36 (CD-36) and augmentation of lipid uptake both of which were inhibited by TUDCA. TUDCA treatment inhibited tunicamycin-induced ER stress as evidenced by the attenuation of phosphorylation of eukaryotic translation initiation factor-2a and glucose reactive protein-78. In addition, TUDCA improved insulin signaling in macrophages by augmenting Akt phosphorylation and blunting c-Jun N-terminal kinase activity.
Inhibition of macrophage ER stress may represent a potential strategy in preventing atherogenesis under diabetic conditions.
背景/目的：最近的证据表明，糖尿病条件下引发的内质网（ER）应激会增加巨噬细胞上清道夫受体的表达，促进氧化型低密度脂蛋白的摄取和动脉粥样硬化形成。本研究旨在验证化学伴侣熊去氧胆酸（TUDCA）是否可以减轻 ER 应激状态下巨噬细胞中的脂质积累这一假设。
用衣霉素处理培养的人巨噬细胞以诱导 ER 应激。通过油红 O 染色和通过荧光测量评估 Dil-氧化型低密度脂蛋白的细胞摄取来评估 ER 应激状态下巨噬细胞的脂质摄取。通过 Western blot 评估 ER 应激标志物、胰岛素信号分子和清道夫受体的蛋白水平和磷酸化状态。
用 ER 应激原衣霉素处理培养的人巨噬细胞会导致分化簇 36（CD-36）蛋白水平增加，脂质摄取增加，而 TUDCA 可抑制这两种作用。TUDCA 可抑制衣霉素诱导的 ER 应激，表现为真核翻译起始因子 2a 和葡萄糖反应蛋白 78 的磷酸化减弱。此外，TUDCA 通过增加 Akt 磷酸化和抑制 c-Jun N-末端激酶活性来改善巨噬细胞中的胰岛素信号。
抑制巨噬细胞 ER 应激可能代表了预防糖尿病条件下动脉粥样硬化形成的一种潜在策略。
