Isoda, KikuoYoung, James LeroyZirlik, AndreasMacFarlane, LindseyTsuboi, NaotakeGerdes, NorbertSchönbeck, UweLibby, Peter2014-09-042006Isoda, Kikuo, James Leroy Young, Andreas Zirlik, Lindsey Adair MacFarlane, Naotake Tsuboi, Norbert Gerdes, Uwe Schönbeck, and Peter Libby. 2006. “Metformin Inhibits Proinflammatory Responses and Nuclear Factor-\(\kappa\)B in Human Vascular Wall Cells.” Arteriosclerosis, Thrombosis, and Vascular Biology 26 (3) (December 29): 611–617. doi:10.1161/01.atv.0000201938.78044.75. http://dx.doi.org/10.1161/01.ATV.0000201938.78044.75.1079-56421524-4636http://nrs.harvard.edu/urn-3:HUL.InstRepos:12769849Objective. 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.en-USatherosclerosisdiabetesinflammationinterleukinssmooth muscle cellJournal Article2014-09-0410.1161/01.ATV.0000201938.78044.75