Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome activation in an AMPK dependent manner
Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome activation in an AMPK dependent manner
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Ilexgenin A 通过 AMPK 依赖性方式抑制 TXNIP/NLRP3 炎症小体激活，抑制内质网应激并改善内皮功能障碍
DOI：
10.1016/j.phrs.2015.05.012
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发表时间：
2015-09-01
影响因子：
9.3
通讯作者：
Wen, Xiao-Dong
中科院分区：
文献类型：
--
作者：
Li, Yi;Yang, Jie;Wen, Xiao-Dong
毛冬青皂苷元A是一种天然三萜类化合物，对血脂紊乱具有有益作用。本研究旨在探讨毛冬青皂苷元A对内皮细胞稳态的影响及其机制。棕榈酸（PA）刺激诱导内质网应激（ER应激）和随后的硫氧还蛋白相互作用蛋白（TXNIP）/NLRP 3炎症体激活内皮细胞，导致内皮功能障碍。毛冬青皂苷元A增强LKB 1依赖的AMPK活性，并通过抑制ROS相关的TXNIP诱导来改善ER应激。然而，这些作用被AMPK α的敲低所阻断，表明AMPK对于其抑制ER应激的作用是必不可少的。同时，ilexgenin A通过下调NLRP 3和切割半胱天冬酶-1诱导来抑制NLRP 3炎性小体活化，从而减少IL-1 β分泌。它还抑制暴露于PA损伤的炎症和凋亡。与内皮细胞中的这些结果一致，Ilexgenin A减弱了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中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显示，Ilexgenin A的口服给药阻断了ER应激/NLRP 3活化，同时减少了血管内皮中的ROS产生并增加了NO产生，充分证实了Ilexgenin A对体内内皮稳态的有益作用。总之，这些结果表明，ER应激相关的TXNIP/NLRP 3炎性体活化是导致内皮功能障碍的原因，并且Ilexgenin A通过抑制ER应激和TXNIP/NLRP 3炎性体活化以及调节AMPK来改善内皮功能障碍。这一发现表明，Ilexgenin A的应用是有用的肥胖心血管疾病的管理。(C)2015爱思唯尔有限公司版权所有。
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 AMPK alpha, 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-1 beta 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. (C) 2015 Elsevier Ltd. All rights reserved.