Resveratrol inhibits inflammation and ameliorates insulin resistant endothelial dysfunction via regulation of AMP-activated protein kinase and sirtuin 1 activities

Background Resveratrol is a phytoalexin with beneficial effects on human health. The aim of the present study was to investigate the effects of resveratrol on endothelial dysfunction involved in insulin signaling and inflammation. Methods Endothelial cells were stimulated with palmitate (PA) to induce insulin resistance characterized by a loss of insulin‐mediated nitric oxide (NO) production. Diabetes was induced in rats by fructose feeding. The effects of resveratrol and the mechanisms involved were investigated using an aortic relaxation assay and Western blot analysis. Results In endothelial cells, 0.1–10 μmol/L resveratrol suppressed IκB kinase β (IKKβ)/nuclear factor‐κB phosphorylation, as well as tumor necrosis factor‐α and interleukin‐6 production, and restored the insulin receptor substrate‐1 (Irs‐1)/Akt/endothelial NO synthase signaling pathway. Furthermore, resveratrol effectively inhibited the mitogenic actions of insulin by decreasing the secretion of endothelin‐1 and plasminogen activator inhibitor‐1. It also positively regulated AMP‐activated kinase (AMPK) and sirtuin 1 (SIRT1) activation, which contributed to the inhibition of inflammation implicated in endothelial insulin resistance. Stimulation with PA and long term‐fructose feeding impaired insulin‐mediated vessel dilation in rat aorta, whereas pretreatment of aortic rings with resveratrol (0.1–10 μmol/L) or treatment of rats with 5 or 20 mg/kg resveratrol counteracted these changes. Conclusion The results indicate that resveratrol inhibits inflammation and facilitates insulin phosphatidylinositol 3‐kinase signaling by beneficial modulation of IRS‐1 function partly via regulation of AMPK and SIRT1 activity in the endothelium. 摘要 背景 白藜芦醇是一种植物抗毒素,对人体健康有益,本研究的目的是调查白藜芦醇对胰岛素信号和炎症中内皮功能障碍的影响。方法:使用棕榈酸酯激活内皮细胞,以产生以胰岛素介导的一氧化氮生成减少为特征的胰岛素抵抗。以果糖喂养大鼠并导致糖尿病。使用主动脉舒张试验和免疫印迹分析调查白藜芦醇的作用及相关机制 结果 在内皮细胞中,0.1–10 μmol/L的白藜芦醇抑制IκB激酶β/核因子‐κB磷酸化以及肿瘤坏死因子‐α和白介素‐6的生成,修复胰岛素受体底物‐1/Akt/内源性一氧化氮合成酶信号通路。白藜芦醇还能通过减少内皮素‐1和纤溶酶原激活物抑制剂‐1的分泌有效抑制胰岛素有丝分裂。它还能有效调节AMP活化激酶和组蛋白去乙酰化酶‐1活性,这与内皮胰岛素抵抗相关的炎症抑制有关。棕榈酸酯刺激和长期果糖喂养导致胰岛素介导的大鼠动脉血管舒张受损,而对主动脉环以0.1–10 μmol/L的白藜芦醇进行预治疗或给予大鼠5或20 mg/kg的白藜芦醇进行治疗可以对抗这种变化。 结论 本研究结果显示白藜芦醇抑制炎症和易化胰岛素磷脂酰肌醇3‐激酶信号部分是通过调节内皮细胞的AMP活化蛋白激酶和组蛋白去乙酰化酶‐1活性以改善去乙酰化酶1功能而实现的。