Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway

Background: Oxidative stress induced by free fatty acids plays a critical role in the pathogenesis of endothelial dysfunction and atherosclerosis in patients with metabolic syndrome. Reducing oxidative stress in these patients may prevent cardiovascular complications. The antidiabetic agent metformin has been reported to directly protect the cardiovascular system. In this study, we examined the effect of metformin on the intracellular levels of reactive oxygen species (ROS) induced by palmitic acid (PA) in human aortic endothelial cells and studied the molecular mechanisms involved. Methods and results: We observed that metformin significantly reduced intracellular ROS levels induced by PA. Additionally, metformin increased the expression of the antioxidant thioredoxin (Trx), which mediated metformin's effects on ROS reduction. Metformin increased Trx expression through the AMP-activated protein kinase (AMPK) pathway. Metformin-regulated Trx at the transcriptional level and forkhead transcription factor 3 (FOXO3) was involved in this process. Conclusion: These results suggest that metformin reduces ROS levels by inducing Trx expression through activation of the AMPK-FOXO3 pathway. (C) 2010 Elsevier Inc. All rights reserved.