This study evaluated peroxisome proliferator-activated receptor (PPAR) delta as a potential target for therapeutic intervention in Ang II-induced senescence in human vascular smooth muscle cells (hVSMCs). Activation of PPAR delta by GW501516, a specific agonist of PPAR delta, significantly inhibited the Ang II-induced premature senescence of hVSMCs. Agonist-activated PPAR delta suppressed the generation of Ang II-triggered reactive oxygen species (ROS) with a concomitant reduction in DNA damage. Notably, GW501516 up-regulated the expression of antioxidant genes, such as glutathione peroxidase 1, thioredoxin 1, manganese superoxide dismutase and heme oxygenase 1. siRNA-mediated down-regulation of these antioxidant genes almost completely abolished the effects of GW501516 on ROS production and premature senescence in hVSMCs treated with Ang II. Taken together, the enhanced transcription of antioxidant genes is responsible for the PPAR delta-mediated inhibition of premature senescence through sequestration of ROS in hVSMCs treated with Ang II. (C) 2011 Elsevier Inc. All rights reserved.