The Role of Nrf2 Signaling in PPARβ/δ-Mediated Vascular Protection against Hyperglycemia-Induced Oxidative Stress Jiménez, Rosario Toral Jiménez, Marta Gómez Guzmán, Manuel Romero Pérez, Miguel Sánchez, Manuel Mahmoud, Ayman M. Duarte, Juan Nrf2 PPAR Hyperglycemia Diabetes Oxidative Stress HUVECs 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 PPARβ/δ agonists GW0742 and L165041. Both PPARβ/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 PPARβ/δ agonists were reversed by either pharmacological inhibition or siRNA-based downregulation of PPARβ/δ. These in vitro findings were confirmed in diabetic rats treated with GW0742. In conclusion, PPARβ/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, PPARβ/δ activation could be of interest to prevent the progression of diabetic vascular complications. 2019-07-05T08:00:27Z 2019-07-05T08:00:27Z 2018-07-25 info:eu-repo/semantics/article 30046379 http://hdl.handle.net/10481/56303 10.1155/2018/5852706 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España Hindawi