Metformin attenuates fluctuating glucose-induced endothelial dysfunction through enhancing GTPCH1-mediated eNOS recoupling and inhibiting NADPH oxidase
Metformin attenuates fluctuating glucose-induced endothelial dysfunction through enhancing GTPCH1-mediated eNOS recoupling and inhibiting NADPH oxidase
复制标题
二甲双胍通过增强 GTPCH1 介导的 eNOS 重新偶联和抑制 NADPH 氧化酶来减轻波动性葡萄糖诱导的内皮功能障碍
DOI：
10.1016/j.jdiacomp.2016.04.018
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发表时间：
2016-08-01
影响因子：
3
通讯作者：
Hong, Tianpei
中科院分区：
文献类型：
--
作者：
An, Huijie;Wei, Rui;Hong, Tianpei
目的：本研究的目的是探讨二甲双胍是否以及如何改善人脐静脉内皮细胞 (HUVEC) 中由波动葡萄糖 (FG) 引起的内皮功能障碍。方法：将暴露于 FG 诱导内皮功能障碍的 HUVEC 与一氧化氮合酶 (NOS) 抑制剂 N-硝基-L-精氨酸甲酯 (L-NAME)、烟酰胺腺嘌呤一起孵育磷酸二核苷酸 (NADPH) 氧化酶抑制剂罗布麻宁、二甲双胍和/或单磷酸腺苷激活蛋白激酶 (AMPK) 抑制剂化合物 C。评估氧化应激和内皮型一氧化氮合酶 (eNOS) 偶联。结果：FG 诱导内皮功能障碍，表现为活性氧 (ROS) 生成增加和一氧化氮 (NO) 生成减少。尽管 FG 增加了 eNOS 磷酸化，但鸟苷 5'-三磷酸环水解酶 1 (GTPCH1) 和四氢生物蝶呤 (BH4) 水平下调证明了未偶联的 eNOS。 FG 还上调了 p47-phox（NADPH 氧化酶的一个亚基）的水平。与 L-NAME 和罗布麻宁相似，二甲双胍通过减少 ROS 的产生来改善 FG 诱导的内皮功能障碍。此外，二甲双胍通过上调 GTPCH1 和 BH4 水平重新偶联 eNOS，并减弱 FG 处理的 HUVEC 中 p47-phox 的上调。化合物C的加入消除了二甲双胍的上述作用。结论：二甲双胍改善了FG诱导的HUVEC内皮功能障碍。二甲双胍的保护作用可能是通过激活 GTPCH1 介导的 eNOS 重新偶联和通过 AMPK 依赖性途径抑制 NADPH 氧化酶来介导的。 (C) 2016 年作者。由爱思唯尔公司出版
Aims: The aim of this study was to investigate whether and how metformin ameliorated endothelial dysfunction induced by fluctuating glucose (FG) in human umbilical vein endothelial cells (HUVECs).Methods: HUVECs, which were exposed to FG to induce endothelial dysfunction, were incubated with nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine-methyl ester (L-NAME), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin, metformin and/or adenosine monophosphate-activated protein kinase (AMPK) inhibitor compound C. The oxidative stress and endothelial NOS (eNOS) coupling were evaluated.Results: FG induced endothelial dysfunction as indicated by increased reactive oxygen species (ROS) generation and decreased nitric oxide (NO) production. Although FG increased eNOS phosphorylation, uncoupled eNOS was evidenced by downregulated guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) and tetrahydrobiopterin (BH4) levels. FG also upregulated the level of p47-phox, a subunit of NADPH oxidase. Similar to L-NAME and apocynin, metformin ameliorated the FG-induced endothelial dysfunction by decreasing ROS generation. Furthermore, metformin recoupled eNOS through upregulating GTPCH1 and BH4 levels, and attenuated the upregulation of p47-phox in FG-treated HUVECs. Addition of compound C abolished the above effects of metformin.Conclusion: Metformin improves the FG-induced endothelial dysfunction in HUVECs. The protective effect of metformin may be mediated through activation of GTPCH1-mediated eNOS recoupling and inhibition of NADPH oxidase via an AMPK-dependent pathway. (C) 2016 The Authors. Published by Elsevier Inc.