title: Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells.
abstract: 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 kappaB (NF-kappaB) 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-kappaB activation and TNF-alpha-induced IkappaB 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-1beta-induced NF-kappaB reporter gene expression. AICAR also suppressed the TNF-alpha- and interleukin-1beta-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 AMPKalpha1 attenuated metformin or AICAR-induced inhibition of NF-kappaB 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-kappaB activation via AMPK activation. Thus, it might be useful to target AMPK signaling in future efforts to prevent atherogenic and inflammatory vascular disease.
authors.affiliation: Department of Endocrinology and Metabolism, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. yhattori@dokkyomed.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hattori
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hattori
authors.forename: Kikuo
authors.initials: K
authors.lastname: Kasai
mesh_terms: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D008687:Metformin / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012265:Ribonucleotides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D012333:RNA, Messenger; D012265:Ribonucleotides; D014409:Tumor Necrosis Factor-alpha; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide