Metformin Inhibits Proinflammatory Responses and Nuclear Factor-κB in Human Vascular Wall Cells

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 26; no. 3; pp. 611 - 617
• Main Authors: Isoda, Kikuo, Young, James L, Zirlik, Andreas, MacFarlane, Lindsey A, Tsuboi, Naotake, Gerdes, Norbert, Schönbeck, Uwe, Libby, Peter
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.03.2006; Hagerstown, MD Lippincott
• Subjects: Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fundamental and applied biological sciences. Psychology; General and cellular metabolism. Vitamins; Medical sciences; Pharmacology. Drug treatments; Vertebrates: cardiovascular system; Endocrinopathy; Human; smooth muscle cell; Diabetes mellitus; Interleukin; Cytokine; Cardiovascular disease; Smooth muscle; Inflammation; interleukins; Vascular disease; Hypoglycemic agent; Biguanides; Atherosclerosis; Metformin; Vascular wall; diabetes
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000201938.78044.75

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.