Jimenez, RosarioToral, MartaGómez-Guzmán, ManuelRomero, MiguelSanchez, ManuelMahmoud, Ayman MDuarte, Juan2023-01-252023-01-252018-06-25http://hdl.handle.net/10668/12758Hyperglycemia 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/AnimalsDiabetes Mellitus, ExperimentalGlucoseHeme Oxygenase-1Human Umbilical Vein Endothelial CellsHumansHyperglycemiaMaleNAD(P)H Dehydrogenase (Quinone)NADPH OxidasesNF-E2-Related Factor 2Oxidative StressPPAR deltaPPAR-betaRatsRats, WistarReactive Oxygen SpeciesSignal TransductionSuperoxidesresearch article30046379open access10.1155/2018/58527061942-0994PMC6036815http://downloads.hindawi.com/journals/omcl/2018/5852706.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036815/pdf