The PPARδ-mediated inhibition of angiotensin II-induced premature senescence in human endothelial cells is SIRT1-dependent

Cellular senescence has been implicated in endothelial dysfunctions affecting vascular tone and regeneration. The molecular mechanisms of vascular senescence are poorly understood. The present study demonstrates that upregulation of SIRT1 by peroxisome proliferator-activated receptor (PPAR) delta attenuates premature senescence in angiotensin (Ang) II-treated human coronary artery endothelial cells (HCAECs). Activation of PPAR delta by the specific ligand GW501516 significantly inhibited Ang II-induced premature senescence and generation of reactive oxygen species (ROS) in HCAECs. A marked concentration- and time-dependent increase in the mRNA levels of SIRT1 was observed in GW501516-treated HCAECs. The effects of GW501516 were almost completely abolished in the presence of small interfering (Si) RNA against PPAR8, indicating that PPAR delta mediates the effects of GW501516. In addition, activation of PPAR delta, but not PPAR delta or PPAR gamma, significantly enhanced SIRT1 promoter activity and protein expression. Down-regulation or inhibition of SIRT1 by siRNA or sirtinol abrogated the effects of PPAR delta on Ang II-induced premature senescence and ROS generation, respectively. Furthermore, resveratrol, a well-known activator of SIRT1, mimicked the action of PPAR delta on Ang II-induced premature senescence and ROS generation. Taken together, these results indicate that the anti-senescent activities of PPAR delta may be achieved at least in part by fine tuning the expression of SIRT1 in the vascular endothelium. (C) 2012 Elsevier Inc. All rights reserved.