Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome activation in an AMPK dependent manner.

Abstract

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.

• Authors: Yi Li, Jie Yang, Mei-Hong Chen, Qiang Wang, Min-Jian Qin, Tong Zhang, Xiao-Qing Chen, Bao-Lin Liu, Xiao-Dong Wen
• Journal: Pharmacological research (Pharmacol Res) Vol. 99 Pg. 101-15 (Sep 2015) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 26054569 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Carrier Proteins
• Drugs, Chinese Herbal
• Inflammasomes
• Reactive Oxygen Species
• Triterpenes
• ilexgenin A
• Thioredoxins
• AMP-Activated Protein Kinases
• Caspase 3

Topics

• AMP-Activated Protein Kinases (deficiency, genetics, metabolism)
• Animals
• Aorta, Thoracic (drug effects, metabolism)
• Apoptosis (drug effects)
• Cardiovascular Diseases (drug therapy, metabolism)
• Carrier Proteins (metabolism)
• Caspase 3 (metabolism)
• Cell Line
• Drugs, Chinese Herbal (pharmacology)
• Endoplasmic Reticulum Stress (drug effects)
• Endothelial Cells (cytology, drug effects, metabolism)
• Gene Knockdown Techniques
• Humans
• Ilex
• Inflammasomes (drug effects, metabolism)
• Lipid Metabolism (drug effects)
• Male
• Mice
• Mice, Inbred ICR
• Mitochondria (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Thioredoxins (metabolism)
• Triterpenes (pharmacology)