Metformin inhibits proinflammatory responses and nuclear factor-κB in human vascular wall cells

Kikuo Isoda, James L. Young, Andreas Zirlik, Lindsey A. MacFarlane, Naotake Tsuboi, Norbert Gerdes, Uwe Schönbeck, Peter Libby

Research output: Contribution to journalArticle

299 Citations (Scopus)

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 (Mφs), and endothelial cells (ECs). Methods and Results - Metformin dose-dependently inhibited IL-1β-induced release of the pro-inflammatory cytokines IL-6 and IL-8 in ECs, SMCs, and Mφs. Investigation of potential signaling pathways demonstrated that metformin diminished IL-1β-induced activation and nuclear translocation of nuclear factor-kappa B (NF-κB) in SMCs. Furthermore, metformin suppressed IL-1β-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 μmol/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-κB 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.

Original languageEnglish
Pages (from-to)611-617
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume26
Issue number3
DOIs
Publication statusPublished - 01-03-2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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