Song Junna, Li Jia, Hou Fangjie, Wang Xiaona, Liu Baolin
Hebei University of Chinese Medicine College of pharmacy teaching and researching section of medicinal plant, Hebei, China.
State Key Laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China; Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicines, Nanjing, China.
Metabolism. 2015 Mar;64(3):428-37. doi: 10.1016/j.metabol.2014.11.008. Epub 2014 Nov 28.
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.
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.
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.
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.
内皮功能障碍与糖尿病患者的心血管并发症密切相关。本研究旨在探讨芒果苷在内质网应激（ER应激）条件下对内皮稳态调节的影响。
高糖（25 mmol/L）暴露诱导内皮细胞产生ER应激并促进活性氧生成。芒果苷通过减弱肌醇需求酶1α（IRE1α）磷酸化和减少活性氧生成，有效抑制与ER应激相关的氧化应激。响应ER应激时，硫氧还蛋白相互作用蛋白（TXNIP）表达增加，随后NLRP3炎性小体激活，白细胞介素-1β（IL-1β）分泌增加。芒果苷处理减弱了TXNIP和NLRP3的表达，并减少了IL-1β和IL-6的产生，表明其对TXNIP/NLRP3炎性小体激活具有抑制作用。NLRP3炎性小体激活是线粒体细胞死亡的原因。芒果苷恢复了线粒体膜电位（Δψm）的丧失并抑制了半胱天冬酶-3活性，从而保护细胞免受高糖诱导的凋亡。此外，当细胞暴露于高糖时，芒果苷抑制内皮素-1（ET-1）分泌并恢复一氧化氮（NO）生成的丧失。芒果苷增强了腺苷酸活化蛋白激酶（AMPK）磷酸化，而AMPK抑制剂化合物C减弱了其有益作用，表明AMPK在其作用中的潜在作用。
我们的研究表明芒果苷对改善内皮稳态具有有益作用，并阐明了芒果苷通过抑制内皮细胞中与ER应激相关的TXNIP/NLRP3炎性小体激活来改善内皮功能障碍的分子途径。
这些发现证明了芒果苷对内皮稳态调节的有益作用，并表明其在糖尿病心血管并发症管理中的潜在应用。
