on January 12, 2006
Published online before print December 29, 2005, doi: 10.1161/01.ATV.0000201938.78044.75
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Submitted on April 7, 2005
Accepted on December 15, 2005
Metformin Inhibits Proinflammatory Responses and Nuclear Factor-
B in Human Vascular Wall Cells
Kikuo Isoda ;
From Donald W. Reynolds Cardiovascular Clinical Research Center (K.I., J.R.Y., A.Z., L.A.M., N.G., U.S., P.L.), Department of Pathology (N.T.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. Current address for U.S.: Research and Development, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Conn.
* To whom correspondence should be addressed. E-mail: plibby{at}rics.bwh.harvard.edu.
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 (MPs), and endothelial cells (ECs).
Methods and Results--Metformin dose-dependently inhibited IL-1
-induced release of the pro-inflammatory cytokines IL-6 and IL-8 in ECs, SMCs, and MPs. Investigation of potential signaling pathways demonstrated that metformin diminished IL-1-induced activation and nuclear translocation of nuclear factor-kappa B (NF-
B). Furthermore, metformin suppressed IL-1-induced activation of the pro-inflammatory phosphokinases Akt, p38, and Erk, but did not affect PI3 kinase 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 PKC in ECs under these conditions.
Conclusions--These data suggest that metformin can exert a direct vascular anti-inflammatory effect by inhibiting NF-B through blockade of the PI3-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.
Key words: atherosclerosis • diabetes • inflammation • interleukins • smooth muscle cell
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