Metformin inhibits cytokine-induced nuclear factor κB activation via AMP-activated protein kinase activation in vascular endothelial cells
Metformin inhibits cytokine-induced nuclear factor κB activation via AMP-activated protein kinase activation in vascular endothelial cells
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DOI：
10.1161/01.hyp.0000221429.94591.72
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发表时间：
2006-06-01
期刊：
影响因子：
8.3
通讯作者：
Kasai, Kikuo
中科院分区：
文献类型：
--
作者：
Hattori, Yoshiyuki;Suzuki, Kunihiro;Kasai, Kikuo
AMP激活的蛋白激酶(AMPK)受细胞内AMP/ATP比例的严格调控，在能量稳态和代谢应激的调节中起着核心作用。二甲双胍已被证明可以激活AMPK。我们假设二甲双胍可以阻止暴露于炎性细胞因子的内皮细胞中核因子-kappaB(NF-kappa B)激活。在人脐静脉内皮细胞(HUVECs)中，观察到二甲双胍能激活AMPK及其下游靶向磷酸乙酰辅酶A羧基酶。二甲双胍还剂量依赖性地抑制肿瘤坏死因子-α诱导的核因子-kappaB活性和肿瘤坏死因子-α诱导的I-kappaB激酶活性。此外，二甲双胍还可抑制肿瘤坏死因子-α诱导的HUVECs中血管细胞黏附分子-1、E-选择素、细胞间黏附分子-1和单核细胞趋化蛋白-1等多种促炎和细胞黏附分子的基因表达。AMPK的药理激活剂5-氨基-4-咪唑甲酰胺核苷(AICAR)可剂量依赖性地抑制肿瘤坏死因子-α和白介素1-β诱导的核因子-kappaB报告基因的表达。AICAR还抑制肿瘤坏死因子-α和白介素1-β诱导的血管细胞黏附分子-1、E-选择素、细胞间黏附分子-1和单核细胞趋化蛋白-1的基因表达。AMPKα1的小干扰RNA可减弱二甲双胍或AICAR对肿瘤坏死因子-α诱导的NF-kappa B活化的抑制作用，提示AMPK可能在细胞炎症调控中发挥作用。根据这些发现，我们认为二甲双胍通过AMPK激活抑制了核因子-kappaB的激活，从而减弱了细胞因子诱导的促炎和黏附分子基因的表达。因此，在未来预防动脉粥样硬化和炎症性血管疾病的努力中，靶向AMPK信号可能是有用的。
AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in regulation of energy homeostasis and metabolic stress. Metformin has been shown to activate AMPK. We hypothesized that metformin may prevent nuclear factor kappa B (NF-kappa B) activation in endothelial cells exposed to inflammatory cytokines. Metformin was observed to activate AMPK, as well as its downstream target, phosphoacetyl coenzyme A carboxylase, in human umbilical vein endothelial cells (HUVECs). Metformin also dose-dependently inhibited tumor necrosis factor (TNF)-alpha induced NF-kappa B activation and TNF-alpha-induced I kappa B kinase activity. Furthermore, metformin attenuated the TNF-alpha-induced gene expression of various proinflammatory and cell adhesion molecules, such as vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1, in HUVECs. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR), dose-dependently inhibited TNF-alpha- and interleukin-1 beta-induced NF-kappa B reporter gene expression. AICAR also suppressed the TNF-alpha- and interleukin-1 beta-induced gene expression of vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 in HUVECs. The small interfering RNA for AMPK alpha 1 attenuated metformin or AICAR-induced inhibition of NF-kappa B activation by TNF-alpha, suggesting a possible role of AMPK in the regulation of cell inflammation. In light of these findings, we suggest that metformin attenuates the cytokine-induced expression of proinflammatory and adhesion molecule genes by inhibiting NF-kappa B activation via AMPK activation. Thus, it might be useful to target AMPK signaling in future efforts to prevent atherogenic and inflammatory vascular disease.