Metformin inhibits TNF-α-induced IκB kinase phosphorylation, IκB-α degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation
Journal
International Journal of Cardiology
Journal Volume
134
Journal Issue
2
Pages
169-175
Date Issued
2009
Author(s)
Abstract
Background: 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-α-induced IL-6 production were investigated. Modulation of AMPK and related signal transduction pathways were also performed. Results: TNF-α increased IL-6 secretion by HUVEC in a dose-dependent manner but inhibitors of NF-κB abolished the TNF-α-induced IL-6 production. Pre-treatment with metformin (100-1000?μmol/L) also inhibited TNF-α-induced IL-6 production, phosphorylation of IκB kinase (IKK) α/β and IκB-α degradation. Metformin increased phosphorylation of AMP-activated kinase (AMPK) but wortmannin, a PI3K inhibitor, negated its effects on AMPK phosphorylation and TNF-α-induced IκB-α degradation. AICAR, a direct AMPK activator, had inhibitory effects on TNF-α-induced IL-6 production, similar to that of metformin. Transfection of siRNA against α1-AMPK eradicated the inhibitory effects of metformin on TNF-α-induced IL-6, implying the essential role of AMPK. Conclusions: Metformin had anti-inflammatory effects on endothelial cells and inhibited TNF-α-induced IKKα/β phosphorylation, IκB-α degradation and IL-6 production in HUVEC. This effect was related to PI3K-dependent AMPK phosphorylation. ? 2008 Elsevier Ireland Ltd. All rights reserved.
Subjects
AMP-activated protein kinase; Atherosclerosis; HUVEC; Interleukin-6; Metformin
SDGs
Other Subjects
5 amino 4 imidazolecarboxamide riboside; hydroxymethylglutaryl coenzyme A reductase kinase; I kappa B alpha; I kappa B kinase alpha; I kappa B kinase beta; immunoglobulin enhancer binding protein; interleukin 6; metformin; phosphatidylinositol 3 kinase; pyrrolidine dithiocarbamate; small interfering RNA; tumor necrosis factor alpha; wortmannin; antiinflammatory activity; article; controlled study; cytokine production; cytokine release; dose response; endothelium cell; enzyme degradation; enzyme phosphorylation; human; human cell; priority journal; signal transduction; umbilical vein; upregulation; 1-Phosphatidylinositol 3-Kinase; AMP-Activated Protein Kinases; Anti-Inflammatory Agents; Atherosclerosis; Cells, Cultured; Endothelial Cells; Enzyme Activation; Humans; Hypoglycemic Agents; I-kappa B Kinase; Interleukin-6; Metformin; NF-kappa B; Phosphorylation; RNA, Small Interfering; Signal Transduction; Tumor Necrosis Factor-alpha; Umbilical Veins
Type
journal article