PPARγ Activation Attenuates Hyperglycemia‐Induced Oxidative Stress by Downregulation of NADPH Oxidases in Human Aortic Endothelial Cells

Diabetic vascular complications are related, in part, to hyperglycemia‐induced oxidative stress. We reported that the PPARγ ligand, rosiglitazone (RSG), reduced expression & activity of aortic reactive oxygen species (ROS)‐generating enzymes, NADPH oxidases, in a mouse model of type 2 diabetes. However, the mechanisms underlying these anti‐oxidative effects of RSG remain to be defined. We hypothesized that RSG acts directly on the endothelium to modulate vascular responses in diabetes. To test this hypothesis, in vitro studies were conducted using human aortic endothelial cells (HAEC) exposed to normal (NG, 5.6 mM) or high (HG, 30 mM) glucose concentrations (24–72 hrs). HG promoted monocyte binding to HAEC. Treatment with either the ROS scavenger, TEMPOL, or the non‐specific NADPH oxidase inhibitor, diphenyleneiodonium, or RSG reduced monocyte binding. RSG also reduced HG‐mediated increases in ROS generation, NADPH oxidase expression & NFκB activation. Similar to RSG, the NFκB inhibitor, CAPE, reduced HG‐induced monocyte binding, ROS generation & NADPH oxidase expression. These findings indicate that PPARγ activation attenuated hyperglycemia‐induced endothelial activation by NFκB‐mediated downregulation of NADPH oxidases. These results suggest that PPARγ is a novel target to modulate endothelial responses to hyperglycemia. Atlanta VA Research Service & NIH RO1 # DK074518