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

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