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. 2006 Mar;26(3):611-7.
doi: 10.1161/01.ATV.0000201938.78044.75. Epub 2005 Dec 29.

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

Kikuo Isoda  1 , James L Young, Andreas Zirlik, Lindsey A MacFarlane, Naotake Tsuboi, Norbert Gerdes, Uwe Schönbeck, Peter Libby
Affiliations

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

Kikuo Isoda et al. Arterioscler Thromb Vasc Biol. 2006 Mar.

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).

Methods and 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.

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