State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Pharmacol Res. 2015 Sep;99:101-15. doi: 10.1016/j.phrs.2015.05.012. Epub 2015 Jun 6.
Ilexgenin A is a natural triterpenoid with beneficial effects on lipid disorders. This study aimed to investigate the effects of ilexgenin A on endothelial homeostasis and its mechanisms. Palmitate (PA) stimulation induced endoplasmic reticulum stress (ER stress) and subsequent thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation in endothelial cells, leading to endothelial dysfunction. Ilexgenin A enhanced LKB1-dependent AMPK activity and improved ER stress by suppression of ROS-associated TXNIP induction. However, these effects were blocked by knockdown of AMPKα, indicating AMPK is essential for its action in suppression of ER stress. Meanwhile, ilexgenin A inhibited NLRP3 inflammasome activation by down-regulation of NLRP3 and cleaved caspase-1 induction, and thereby reduced IL-1β secretion. It also inhibited inflammation and apoptosis exposed to PA insult. Consistent with these results in endothelial cells, ilexgenin A attenuated ER stress and restored the loss of eNOS activity in vascular endothelium, and thereby improved endothelium-dependent vasodilation in rat aorta. A further analysis in high-fat fed mice showed that oral administration of ilexgenin A blocked ER stress/NLRP3 activation with reduced ROS generation and increased NO production in vascular endothelium, well confirming the beneficial effect of ilexgenin A on endothelial homeostasis in vivo. Taken together, these results show ER stress-associated TXNIP/NLRP3 inflammasome activation was responsible for endothelial dysfunction and ilexgenin A ameliorated endothelial dysfunction by suppressing ER-stress and TXNIP/NLRP3 inflammasome activation with a regulation of AMPK. This finding suggests that the application of ilexgenin A is useful in the management of cardiovascular diseases in obesity.
冬青苷 A 是一种具有改善脂质紊乱有益作用的天然三萜类化合物。本研究旨在探讨冬青苷 A 对血管内皮稳态的影响及其机制。软脂酸（PA）刺激可诱导内皮细胞内质网应激（ER 应激）和随后的硫氧还蛋白相互作用蛋白（TXNIP）/NLRP3 炎性小体激活，导致内皮功能障碍。冬青苷 A 通过抑制 ROS 相关的 TXNIP 诱导增强 LKB1 依赖性 AMPK 活性并改善 ER 应激。然而，这些作用被 AMPKα 的敲低所阻断，表明 AMPK 对于其抑制 ER 应激的作用是必需的。同时，冬青苷 A 通过下调 NLRP3 和裂解的 caspase-1 诱导抑制 NLRP3 炎性小体激活，从而减少 IL-1β 的分泌。它还抑制了 PA 损伤暴露下的炎症和细胞凋亡。与内皮细胞中的这些结果一致，冬青苷 A 减轻了 ER 应激并恢复了血管内皮中 eNOS 活性的丧失，从而改善了大鼠主动脉的内皮依赖性血管舒张。在高脂肪喂养的小鼠中的进一步分析表明，口服冬青苷 A 通过减少血管内皮中的 ROS 生成和增加 NO 生成来阻断 ER 应激/NLRP3 激活，很好地证实了冬青苷 A 对体内血管内皮稳态的有益作用。总之，这些结果表明 ER 应激相关的 TXNIP/NLRP3 炎性小体激活是导致内皮功能障碍的原因，而冬青苷 A 通过抑制 ER 应激和 TXNIP/NLRP3 炎性小体激活以及调节 AMPK 来改善内皮功能障碍。这一发现表明，冬青苷 A 的应用在肥胖相关心血管疾病的管理中是有用的。
