Person:

Libby, Peter

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.

To determine whether nuclear factor (NF)-(\kappa) B is necessary to confer endothelial cell responsiveness to interferon (INF)-(\gamma) in terms of vascular cell adhesion molecule (VCAM)-1 expression and leukocyte adhesion, human endothelial cells were treated with IFN-(\gamma) in the presence of low concentrations (LCs) of interleukin (IL)-1(\alpha) (≤100 pg/mL), which activates (NF-\kappa B) but does not induce VCAM-1 expression. Although IFN-(\gamma) induced major histocompatibility complex class II antigen expression and although a high concentration of IL-1(\alpha) (10 ng/mL) induced leukocyte adhesion and VCAM-1 expression, neither IFN-(\gamma) nor LC IL-1(\alpha) was able to induce VCAM-1 expression or leukocyte adhesion. However, the combination of IFN-(\gamma) and LC IL-1(\alpha) induced VCAM-1 expression and increased leukocyte adhesion (67% and 49% of high-concentration IL-1(\alpha), respectively). Electrophoretic mobility shift assays and immunoblotting of nuclear extracts showed that IFN-(\gamma) activated signal transducers and activators of transcription (STAT)-1(\alpha) and interferon regulatory factor (IRF)-1 but not (NF-\kappa B), whereas LC IL-1(\alpha) activated (NF-\kappa B) but not STAT-1(\alpha) or IRF-1. Nuclear run-on studies showed that LC IL-1(\alpha) is necessary but not sufficient for inducing VCAM-1 gene transcription and that the combination of IFN-(\gamma) and LC IL-1(\alpha) is required for full VCAM-1 gene transcription. These findings suggest that factors that activate (NF-\kappa B) can synergize with IFN-(\gamma) in promoting endothelial-leukocyte interaction.