Mangiferin inhibits endoplasmic reticulum stress-associated thioredoxin-interacting protein/NLRP3 inflammasome activation with regulation of AMPK in endothelial cells

• Published in: Metabolism, clinical and experimental Vol. 64; no. 3; pp. 428 - 437
• Main Authors: Song, Junna, Li, Jia, Hou, Fangjie, Wang, Xiaona, Liu, Baolin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2015
• Subjects: AMPK; Apoptosis - drug effects; Carrier Proteins - metabolism; Cytokines - metabolism; Endocrinology & Metabolism; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Endoribonucleases - metabolism; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Endothelial Cells - metabolism; Endothelial dysfunction; Human Umbilical Vein Endothelial Cells; Humans; Hypoglycemic Agents - pharmacology; Inflammation - metabolism; Mangiferin; MAP Kinase Signaling System - drug effects; Membrane Potential, Mitochondrial - drug effects; Nitric Oxide - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein; Protein-Serine-Threonine Kinases - metabolism; Reactive Oxygen Species - metabolism; Xanthones - pharmacology; ER stress; AICA riboside; thioredoxin-interacting protein; endoplasmic reticulum stress; AMP-kinase; TG; ET-1; NOD-like receptor pyrin domain containing-3; ROS; reactive oxygen species; IRE1α; Endothelial dysfunction; NLRP3; TXNIP; AMPK; AICAR; endothelin-1; thapsigargin; inositol-requiring enzyme-1α; Mangiferin; Endoplasmic reticulum stress
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2014.11.008

Abstract Background Endothelial dysfunction is tightly associated with cardiovascular complications in diabetic patients. This study aims to investigate the effects of mangiferin on the regulation of endothelial homeostasis under endoplasmic reticulum stress (ER stress) conditions. Results High glucose (25 mmol/L) exposure induced ER stress and promoted ROS production in endothelial cells. Mangiferin effectively inhibited ER stress-associated oxidative stress by attenuating IRE1α phosphorylation and reducing ROS production. In response to ER stress, thioredoxin-interacting protein (TXNIP) expression increased, followed by NLRP3 inflammasome activation and increased IL-1β secretion. Mangiferin treatment attenuated the expressions of TXNIP and NLRP3 and reduced IL-1β and IL-6 production, demonstrating its inhibitory effects on TXNIP/NLRP3 inflammasome activation. NLRP3 inflammasome activation is responsible for mitochondrial cell death. Mangiferin restored the loss of the mitochondrial membrane potential ( Δψm ) and inhibited caspase-3 activity, and thereby protected cells from high glucose-induced apoptosis. Moreover, mangiferin inhibited ET-1 secretion and restored the loss of NO production when cells were exposed to high glucose. Mangiferin enhanced AMPK phosphorylation and AMPK inhibitor compound C diminished its beneficial effects, indicating the potential role of AMPK in its action. Conclusion Our work showed the beneficial effects of mangiferin on the improvement of endothelial homeostasis and elucidated the molecular pathway through which mangiferin ameliorated endothelial dysfunction by inhibition of ER stress-associated TXNIP/NLRP3 inflammasome activation in endothelial cells. Significance These findings demonstrated the beneficial effects of mangiferin on the regulation of endothelial homeostasis and indicated its potential application in the management of diabetic cardiovascular complications.