Chen Min, Ren Lina, Meng Yanyan, Shi Liye, Chen Ling, Yu Bo, Wu Qianqian, Qi Guoxian
a Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
b Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
Can J Physiol Pharmacol. 2018 Feb;96(2):120-127. doi: 10.1139/cjpp-2017-0016. Epub 2017 Aug 30.
Oxidized low-density lipoprotein (ox-LDL)-induced endothelial dysfunction in human vascular endothelial cells contributes to the development of atherosclerosis. E64d, a cysteine protease inhibitor, blocks the elastolytic activity of cathepsin essential for vascular matrix remodeling and reduces neurovascular endothelial apoptosis. The objective of this study was to investigate the effects and the underling mechanisms of E64d on ox-LDL-induced endothelial dysfunction in human aortic endothelial cells (HAECs). HAECs were treated with various concentrations of ox-LDL (0-200 mg/L) for 24 h with or without E64d. The results showed that E64d attenuated ox-LDL-induced increase in soluble intercellular adhesion molecule-1 (sICAM-1) concentration and reduction in endothelial nitric oxide synthase (eNOS) expression, prevented ox-LDL-induced reduction in cell viability and migration ability of HAECs. E64d decreased the protein expression of cathepsin B (CTSB), Beclin 1, and microtubule-associated protein light chain 3 (LC3)-II, but not p62. LC3 puncta and autophagosome formation were also reduced by E64d in HAECs. Moreover, E64d decreased the production of MDA and increased the activity of SOD. The results showed that E64d ameliorated ox-LDL-induced endothelial dysfunction in HAECs.
氧化型低密度脂蛋白（ox-LDL）诱导人血管内皮细胞功能障碍，这在动脉粥样硬化的发展过程中起作用。E64d是一种半胱氨酸蛋白酶抑制剂，可阻断组织蛋白酶对血管基质重塑至关重要的弹性蛋白水解活性，并减少神经血管内皮细胞凋亡。本研究的目的是探讨E64d对ox-LDL诱导的人主动脉内皮细胞（HAECs）功能障碍的影响及潜在机制。将HAECs用不同浓度的ox-LDL（0 - 200 mg/L）处理24小时，同时或不同时添加E64d。结果表明，E64d减弱了ox-LDL诱导的可溶性细胞间黏附分子-1（sICAM-1）浓度升高和内皮型一氧化氮合酶（eNOS）表达降低，防止了ox-LDL诱导的HAECs细胞活力和迁移能力下降。E64d降低了组织蛋白酶B（CTSB）、Beclin 1和微管相关蛋白轻链3（LC3）-II的蛋白表达，但不影响p62。E64d还减少了HAECs中的LC3斑点和自噬体形成。此外，E64d降低了丙二醛（MDA）的产生并增加了超氧化物歧化酶（SOD）的活性。结果表明，E64d改善了ox-LDL诱导的HAECs内皮功能障碍。
