A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells (Retracted article. See vol. 55, pg. 533, 2012)
A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells (Retracted article. See vol. 55, pg. 533, 2012)
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DOI：
10.1007/s00125-010-1831-8
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发表时间：
2010-10-01
期刊：
影响因子：
8.2
通讯作者：
Hayashi, T.
中科院分区：
文献类型：
--
作者：
Hattori, Y.;Jojima, T.;Hayashi, T.
胰高血糖素样肽-1（GLP-1）是胰高血糖素原衍生肽家族的成员，在临床前和临床研究中被认为对心血管功能具有有利的作用。GLP-1调节心血管功能的机制复杂且尚未完全了解。因此，我们研究了GLP-1类似物利拉鲁肽是否对血管内皮细胞具有保护作用，利拉鲁肽是酰化的GLP-1，用自动一氧化氮检测器测量培养基中的亚硝酸盐和硝酸盐。通过评估酶的磷酸化状态和通过瓜氨酸合成评估eNOS活性来评估内皮型一氧化氮合酶（eNOS）活化。核因子-κ B（NF-κ B）激活通过报告基因测定进行评估。它还引起eNOS磷酸化，增强eNOS活性，并恢复了精氨酸诱导的eNOS（也称为NOS 3）mRNA水平下调，这依赖于NF-κ B激活。因此，我们研究了利拉鲁肽对TNF α诱导的NF-κ B B活化和NF-κ B依赖性促炎基因表达的影响。利拉鲁肽以剂量依赖性方式抑制NF-κ B活化和TNF α诱导的I κ B降解。它还降低了TNF α诱导的MCP-1（也称为CCL 2），VCAM 1，ICAM 1和E-选择素mRNA的表达。AMP活化蛋白激酶（AMPK）抑制剂化合物C或AMPK（也称为PRKAA 1）小干扰RNA可减弱利拉鲁肽诱导的一氧化氮生成增强和NF-κ B活化抑制。事实上，利拉鲁肽诱导AMPK的磷酸化，这是通过不依赖于环AMP的信号传导途径发生的。利拉鲁肽通过增加一氧化氮的产生和抑制NF-κ B活化（至少部分通过AMPK活化）对血管内皮细胞发挥抗炎作用。这些作用可能解释了利拉鲁肽的一些观察到的血管保护特性及其对心血管系统的有益作用。
Glucagon-like peptide-1 (GLP-1), a member of the proglucagon-derived peptide family, was seen to exert favourable actions on cardiovascular function in preclinical and clinical studies. The mechanisms through which GLP-1 modulates cardiovascular function are complex and incompletely understood. We thus investigated whether the GLP-1 analogue, liraglutide, which is an acylated GLP-1, has protective effects on vascular endothelial cells.Nitrite and nitrate were measured in medium with an automated nitric oxide detector. Endothelial nitric oxide synthase (eNOS) activation was assessed by evaluating the phosphorylation status of the enzyme and evaluating eNOS activity by citrulline synthesis. Nuclear factor kappa B (NF-kappa B) activation was assessed by reporter gene assay.Liraglutide dose-dependently increased nitric oxide production in HUVECs. It also caused eNOS phosphorylation, potentiated eNOS activity and restored the cytokine-induced downregulation of eNOS (also known as NOS3) mRNA levels, which is dependent on NF-kappa B activation. We therefore examined the effect of liraglutide on TNF alpha-induced NF-kappa B activation and NF-kappa B-dependent expression of proinflammatory genes. Liraglutide dose-dependently inhibited NF-kappa B activation and TNF alpha-induced I kappa B degradation. It also reduced TNF alpha-induced MCP-1 (also known as CCL2), VCAM1, ICAM1 and E-selectin mRNA expression. Liraglutide-induced enhancement of nitric oxide production and suppression of NF-kappa B activation were attenuated by the AMP-activated protein kinase (AMPK) inhibitor compound C or AMPK (also known as PRKAA1) small interfering RNA. Indeed, liraglutide induced phosphorylation of AMPK, which occurs through a signalling pathway independent of cyclic AMP.Liraglutide exerts an anti-inflammatory effect on vascular endothelial cells by increasing nitric oxide production and suppressing NF-kappa B activation, partly at least through AMPK activation. These effects may explain some of the observed vasoprotective properties of liraglutide, as well as its beneficial effects on the cardiovascular system.