Irisin Alleviates Advanced Glycation End Products-Induced Inflammation and Endothelial Dysfunction via Inhibiting ROS-NLRP3 Inflammasome Signaling
Irisin Alleviates Advanced Glycation End Products-Induced Inflammation and Endothelial Dysfunction via Inhibiting ROS-NLRP3 Inflammasome Signaling
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DOI：
10.1007/s10753-017-0685-3
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发表时间：
2018-02-01
期刊：
影响因子：
5.1
通讯作者：
He, Yan-Zheng
中科院分区：
文献类型：
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作者：
Deng, Xian;Huang, Wei;He, Yan-Zheng
NLR家族pyrin domain containing 3（NLRP 3）炎性体的激活参与动脉粥样硬化的发生和发展。最近的研究表明，鸢尾素，一个新发现的脂肪细胞因子，减轻内皮功能障碍，在2型糖尿病部分通过减少氧化/硝化应激，表明鸢尾素可能是一个有前途的候选人，用于治疗糖尿病血管并发症。然而，Irisin和NLRP 3炎性小体在动脉粥样硬化发病机制中的关系尚不清楚。在本研究中，我们培养人脐静脉内皮细胞（HUVECs）在晚期糖基化终产物（AGEs）培养基中，外源性鸢尾素（0.01，0.1，1 μ g/ml）作为干预试剂。构建siRNA和腺病毒载体，实现NLRP 3基因的沉默和过表达。我们的数据显示，鸢尾素显著逆转AGEs诱导的氧化应激和NLRP 3炎性信号转导激活（p < 0.05），并以剂量依赖性方式增加内皮型一氧化氮合酶（eNOS）和一氧化氮（NO）的产生（p < 0.05）。siRNA介导的NLRP 3敲低促进了鸢尾素介导的抗炎和抗动脉粥样硬化作用（p < 0.05）。然而，这些鸢尾素介导的作用被过表达NLRP 3逆转（p < 0.05）。总而言之，我们的结果表明，鸢尾素通过抑制ROS-NLRP 3炎性体信号传导来缓解AGEs诱导的炎症和内皮功能障碍，表明鸢尾素诱导糖尿病血管并发症治疗作用的可能机制。
The activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome have been implicated in the initiation or progression of atherosclerosis. Recent research showed that irisin, a newly discovered adipomiokine, alleviates endothelial dysfunction in type 2 diabetes partially via reducing oxidative/nitrative stresses, suggesting that irisin may be a promising candidate for the treatment of vascular complications of diabetes. However, the association between irisin and NLRP3 inflammasome in the pathogenesis of atherosclerosis remains unclear. In the present study, we cultured human umbilical vein endothelial cells (HUVECs) in advanced glycation end products (AGEs) medium; exogenous irisin (0.01, 0.1, 1 mu g/ml) were used as an intervention reagent. siRNA and adenoviral vector were constructed to realize silencing and over-expression of NLRP3 gene. Our data showed that irisin significantly reversed AGEs-induced oxidative stress and NLRP3 inflammasome signaling activation (p < 0.05), and increased the endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production in a dose-dependent manner (p < 0.05). siRNA-mediated knockdown NLRP3 facilitated the irisin-mediated anti-inflammatory and antiatherogenic effects (p < 0.05). However, these irisin-mediated effects were reversed by over-expression NLRP3 (p < 0.05). Taken together, our results reveal that irisin alleviates AGEs-induced inflammation and endothelial dysfunction via inhibiting ROS-NLRP3 inflammasome signaling, suggest a likely mechanism for irisin-induced therapeutic effect in vascular complications of diabetes.