title: Transcriptional up-regulation of antioxidant genes by PPARδ inhibits angiotensin II-induced premature senescence in vascular smooth muscle cells.
abstract: This study evaluated peroxisome proliferator-activated receptor (PPAR) δ as a potential target for therapeutic intervention in Ang II-induced senescence in human vascular smooth muscle cells (hVSMCs). Activation of PPARδ by GW501516, a specific agonist of PPARδ, significantly inhibited the Ang II-induced premature senescence of hVSMCs. Agonist-activated PPARδ 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 PPARδ-mediated inhibition of premature senescence through sequestration of ROS in hVSMCs treated with Ang II.
authors.affiliation: Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, South Korea.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Ham
authors.forename: Kyung Shin
authors.initials: KS
authors.lastname: Paek
authors.forename: Jung Seok
authors.initials: JS
authors.lastname: Hwang
authors.forename: Si Young
authors.initials: SY
authors.lastname: Jung
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Hanna
authors.initials: H
authors.lastname: Jin
authors.forename: Eun Sil
authors.initials: ES
authors.lastname: Kang
authors.forename: Im Sun
authors.initials: IS
authors.lastname: Woo
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jae Heun
authors.initials: JH
authors.lastname: Lee
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
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 / Q000494:pharmacology / Q000502:physiology; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D047494:PPAR delta / Q000819:agonists / Q000096:biosynthesis / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology; D013879:Thioredoxins / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation; D000094765:Glutathione Peroxidase GPX1
chemical_list: C425931:GW 501516; D047494:PPAR delta; D017382:Reactive Oxygen Species; C491203:TXN protein, human; D013844:Thiazoles; D000804:Angiotensin II; D013879:Thioredoxins; D005979:Glutathione Peroxidase; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human