TY - JOUR
T1 - Metformin inhibits proinflammatory responses and nuclear factor-κB in human vascular wall cells
AU - Isoda, Kikuo
AU - Young, James L.
AU - Zirlik, Andreas
AU - MacFarlane, Lindsey A.
AU - Tsuboi, Naotake
AU - Gerdes, Norbert
AU - Schönbeck, Uwe
AU - Libby, Peter
PY - 2006/3
Y1 - 2006/3
N2 - 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.
AB - 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.
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U2 - 10.1161/01.ATV.0000201938.78044.75
DO - 10.1161/01.ATV.0000201938.78044.75
M3 - Article
C2 - 16385087
AN - SCOPUS:33646105593
SN - 1079-5642
VL - 26
SP - 611
EP - 617
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 3
ER -