title: Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells.
abstract: OBJECTIVE
  Metformin may benefit the macrovascular complications of diabetes independently of its conventional hypoglycemic effects. Accumulating evidence suggests that inflammatory processes participate in type 2 diabetes and its atherothrombotic manifestations. Therefore, this study examined the potential action of metformin as an inhibitor of pro-inflammatory responses in human vascular smooth muscle cells (SMCs), macrophages (Mphis), and endothelial cells (ECs).
  
  
  RESULTS
  Metformin dose-dependently inhibited IL-1beta-induced release of the pro-inflammatory cytokines IL-6 and IL-8 in ECs, SMCs, and Mphis. Investigation of potential signaling pathways demonstrated that metformin diminished IL-1beta-induced activation and nuclear translocation of nuclear factor-kappa B (NF-kappaB) in SMCs. Furthermore, metformin suppressed IL-1beta-induced activation of the pro-inflammatory phosphokinases Akt, p38, and Erk, but did not affect PI3 kinase (PI3K) activity. To address the significance of the anti-inflammatory effects of a therapeutically relevant plasma concentration of metformin (20 micromol/L), we conducted experiments in ECs treated with high glucose. Pretreatment with metformin also decreased phosphorylation of Akt and protein kinase C (PKC) in ECs under these conditions.
  
  
  CONCLUSIONS
  These data suggest that metformin can exert a direct vascular anti-inflammatory effect by inhibiting NF-kappaB through blockade of the PI3K-Akt pathway. The novel anti-inflammatory actions of metformin may explain in part the apparent clinical reduction by metformin of cardiovascular events not fully attributable to its hypoglycemic action.
authors.affiliation: Donald W. Reynolds Cardiovascular Clinical Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Kikuo
authors.initials: K
authors.lastname: Isoda
authors.forename: James L
authors.initials: JL
authors.lastname: Young
authors.forename: Andreas
authors.initials: A
authors.lastname: Zirlik
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: MacFarlane
authors.forename: Naotake
authors.initials: N
authors.lastname: Tsuboi
authors.forename: Norbert
authors.initials: N
authors.lastname: Gerdes
authors.forename: Uwe
authors.initials: U
authors.lastname: Schönbeck
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000276:immunology; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008687:Metformin / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012501:Saphenous Vein / Q000166:cytology
chemical_list: D000893:Anti-Inflammatory Agents; D007004:Hypoglycemic Agents; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose