The Role of Nrf2 Signaling in PPAR β/ δ-Mediated Vascular Protection against Hyperglycemia-Induced Oxidative Stress

Abstract

Hyperglycemia induces oxidative stress and plays a substantial role in the progression of vascular diseases. Here, we demonstrated the potentiality of peroxisome proliferator-activated receptor (PPAR) β/ δ activation in attenuating high glucose-induced oxidative stress in endothelial cells and diabetic rats, pointing to the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2). HUVECs exposed to high glucose showed increased levels of reactive oxygen species (ROS) and upregulated NOX-2, NOX-4, Nrf2, and NQO-1 effects that were significantly reversed by the PPAR β/ δ agonists GW0742 and L165041. Both PPAR β/ δ agonists, in a concentration-dependent manner, induced transcriptional and protein upregulation of heme oxygenase-1 (HO-1) under low- and high-glucose conditions. All effects of PPAR β/ δ agonists were reversed by either pharmacological inhibition or siRNA-based downregulation of PPAR β/ δ. These in vitro findings were confirmed in diabetic rats treated with GW0742. In conclusion, PPAR β/ δ activation confers vascular protection against hyperglycemia-induced oxidative stress by suppressing NOX-2 and NOX-4 expression plus a direct induction of HO-1; with the subsequent downregulation of the Nrf2 pathway. Thus, PPAR β/ δ activation could be of interest to prevent the progression of diabetic vascular complications.