Astragaloside IV Suppresses High Glucose-Induced NLRP3 Inflammasome Activation by Inhibiting TLR4/NF-κB and CaSR

• Published in: Mediators of inflammation Vol. 2019; no. 2019; pp. 1 - 16
• Main Authors: Lu, Meili, Liu, Yang, Zhang, Zhen, Liu, Xinran, Zhang, Yingjie, Leng, Bin, Wang, Hongxin
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Publishing Corporation 01.01.2019; Hindawi; Hindawi Limited
• Subjects: Animals; Anti-inflammatory agents; Aorta; Apoptosis; Atherosclerosis; Biotechnology; Blotting, Western; Calcium-sensing receptors; Cardiovascular diseases; Caspase; Caspase-1; Diabetes; Endothelial cells; Glucose; Glucose - pharmacology; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Hyperglycemia; IL-1β; Inflammasomes; Inflammasomes - drug effects; Inflammasomes - metabolism; Inflammation; Interleukin 18; Interleukin-18 - metabolism; Interleukin-1beta - metabolism; Laboratory animals; Male; NF-kappa B - metabolism; NF-κB protein; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Oral administration; Pharmacology; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing - metabolism; RNA, Small Interfering; Rodents; Saponins - pharmacology; Signal transduction; Streptozocin; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Triterpenes - pharmacology; Umbilical vein; United States > US; China
• ISSN: 0962-9351; 1466-1861
• DOI: 10.1155/2019/1082497

Long-term exposure to high glucose induces vascular endothelial inflammation that can result in cardiovascular disease. Astragaloside IV (As-IV) is widely used for anti-inflammatory treatment of cardiovascular diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of As-IV on high glucose-induced endothelial inflammation and explored its possible mechanisms. In vivo, As-IV (40 and 80 mg/kg/d) was orally administered to rats for 8 weeks after a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33 mM glucose) in the presence or absence of As-IV, NPS2143 (CaSR inhibitor), BAY 11-7082 (NF-κB p65 inhibitor), and INF39 (NLRP3 inhibitor), and overexpression of CaSR was induced by infection of CaSR-overexpressing lentiviral vectors to further discuss the anti-inflammatory property of As-IV. The results showed that high glucose increased the expression of interleukin-18 (IL-18), interleukin-1β (IL-1β), NLRP3, caspase-1, and ASC, as well as the protein level of TLR4, nucleus p65, and CaSR. As-IV can reverse these changes in vivo and in vitro. Meanwhile, NPS2143, BAY 11-7082, and INF39 could significantly abolish the high glucose-enhanced NLRP3, ASC, caspase-1, IL-18, and IL-1β expression in vitro. In addition, both NPS2143 and BAY 11-7082 attenuated high glucose-induced upregulation of NLRP3, ASC, caspase-1, IL-18, and IL-1β expression. In conclusion, this study suggested that As-IV could inhibit high glucose-induced NLRP3 inflammasome activation and subsequent secretion of proinflammatory cytokines via inhibiting TLR4/NF-κB signaling pathway and CaSR, which provides new insights into the anti-inflammatory activity of As-IV.