|Title:||Metformin Inhibits Tnf-Alpha-Induced I Kappa B Kinase Phosphorylation, I Kappa B-Alpha Degradation and Il-6 Production in Endothelial Cells through Pi3k-Dependent Ampk Phosphorylation||Authors:||CHIANG, SHU-HUI
|Keywords:||Metformin;AMP-activated protein kinase;Atherosclerosis;HUVEC;Interleukin-6||Issue Date:||2009||Journal Volume:||v.134||Journal Issue:||n.2||Start page/Pages:||169-175||Source:||INTERNATIONAL JOURNAL OF CARDIOLOGY||Abstract:||
Metformin has been reported to reduce cardiovascular complications in diabetic patients. The purpose of the present study was to investigate the anti-inflammatory effects of metformin on endothelial cells and the related molecular mechanisms. Methods: Human umbilical vein endothelial cells (HUVEC) were used for the experiments. The effects of metformin on TNF-alpha-induced IL-6 production were investigated. Modulation of AMPK and related signal transduction pathways were also performed. Results: TNF - alpha increased IL-6 secretion by HUVEC in a dose-dependent manner but inhibitors of NF-kappa B abolished the TNF-alpha- induced IL-6 production. Pre-treatment with metformin (100- 1000 mu mol/L) also inhibited TNF- alpha-induced IL-6 production, phosphorylation of I kappa B kinase (IKK) alpha/ beta and I kappa B-alpha degradation. Metformin increased phosphorylation of AMP-activated kinase (AMPK) but wortmannin, a PI3K inhibitor, negated its effects on AMPK phosphorylation and TNF-alpha- induced I kappa B-alpha degradation. AICAR, a direct AMPK activator, had inhibitory effects on TNF-alpha-induced IL-6 production, similar to that of metformin. Transfection of siRNA against alpha 1- AMPK eradicated the inhibitory effects of metformin on TNF- alpha-induced IL-6, implying the essential role of AMPK. Conclusions: Metformin had anti-inflammatory effects on endothelial cells and inhibited TNF-alpha-induced IKK alpha/ beta phosphorylation, I kappa B-alpha degradation and IL-6 production in HUVEC. This effect was related to PI3K- dependent AMPK phosphorylation.
|Appears in Collections:||醫學系|
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