title: 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.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mei-Hong
authors.initials: MH
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Min-Jian
authors.initials: MJ
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.affiliation: School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Bao-Lin
authors.initials: BL
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xiaodongwen123@126.com.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Wen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D030017:Ilex; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D004365:Drugs, Chinese Herbal; D058847:Inflammasomes; D017382:Reactive Oxygen Species; D014315:Triterpenes; C468850:ilexgenin A; D013879:Thioredoxins; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3
keywords: AICA riboside (PubChem CID: 17513); AMPK; Acetylcholine (PubChem CID: 75271); BAPTA-AM (PubChem CID: 2293); Compound C (PubChem CID: 11524144); Dimethyl sulfoxide (PubChem CID: 679); Endoplasmic reticulum stress; Endothelial dysfunction; Ilexgenin A; Mitoquinone mesylate (PubChem CID: 11388331); NLRP3 inflammasome; Palmitic acid (PubChem CID: 985); Phenylephrine (PubChem CID: 5284443); Tauroursodeoxycholic acid (PubChem CID: 46782978); Thapsigargin (PubChem CID: 446378)