title: The PPARδ-mediated inhibition of angiotensin II-induced premature senescence in human endothelial cells is SIRT1-dependent.
abstract: 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) δ attenuates premature senescence in angiotensin (Ang) II-treated human coronary artery endothelial cells (HCAECs). Activation of PPARδ 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 PPARδ, indicating that PPARδ mediates the effects of GW501516. In addition, activation of PPARδ, but not PPARα or PPARγ, significantly enhanced SIRT1 promoter activity and protein expression. Down-regulation or inhibition of SIRT1 by siRNA or sirtinol abrogated the effects of PPARδ on Ang II-induced premature senescence and ROS generation, respectively. Furthermore, resveratrol, a well-known activator of SIRT1, mimicked the action of PPARδ on Ang II-induced premature senescence and ROS generation. Taken together, these results indicate that the anti-senescent activities of PPARδ may be achieved at least in part by fine tuning the expression of SIRT1 in the vascular endothelium.
authors.affiliation: Department of Pharmacology, Gyeongsang National University School of Medicine, Jinju 660-701, Republic of Korea.
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Eun Sil
authors.initials: ES
authors.lastname: Kang
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Ham
authors.forename: Jung Seok
authors.initials: JS
authors.lastname: Hwang
authors.forename: Tae Sik
authors.initials: TS
authors.lastname: Yoo
authors.forename: Hanna
authors.initials: H
authors.lastname: Lee
authors.forename: Kyung Shin
authors.initials: KS
authors.lastname: Paek
authors.forename: Chankyu
authors.initials: C
authors.lastname: Park
authors.forename: Hoon Taek
authors.initials: HT
authors.lastname: Lee
authors.forename: Jin-Hoi
authors.initials: JH
authors.lastname: Kim
authors.forename: Chang Woo
authors.initials: CW
authors.lastname: Han
authors.forename: Han Geuk
authors.initials: HG
authors.lastname: Seo
mesh_terms: D000804:Angiotensin II / Q000187:drug effects* / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D047494:PPAR delta / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000502:physiology*
chemical_list: D047494:PPAR delta; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000804:Angiotensin II; C447939:SIRT1 protein, human; D056564:Sirtuin 1