title: Activation of PPARδ counteracts angiotensin II-induced ROS generation by inhibiting rac1 translocation in vascular smooth muscle cells.
abstract: Angiotensin II (Ang II)-mediated modification of the redox milieu of vascular smooth muscle cells (VSMCs) has been implicated in several pathophysiological processes, including cell proliferation, migration and differentiation. In this study, we demonstrate that the peroxisome proliferator-activated receptor (PPAR) δ counteracts Ang II-induced production of reactive oxygen species (ROS) in VSMCs. Activation of PPARδ by GW501516, a specific ligand for PPARδ, significantly reduced Ang II-induced ROS generation in VSMCs. This effect was, however, reversed in the presence of small interfering (si)RNA against PPARδ. The marked increase in ROS levels induced by Ang II was also eliminated by the inhibition of phosphatidylinositol 3-kinase (PI3K) but not of protein kinase C, suggesting the involvement of the PI3K/Akt signalling pathway in this process. Accordingly, ablation of Akt with siRNA further enhanced the inhibitory effects of GW501516 in Ang II-induced superoxide production. Ligand-activated PPARδ also blocked Ang II-induced translocation of Rac1 to the cell membrane, inhibiting the activation of NADPH oxidases and consequently ROS generation. These results indicate that ligand-activated PPARδ plays an important role in the cellular response to oxidative stress by decreasing ROS generated by Ang II in vascular cells.
authors.affiliation: Department of Animal Biotechnology, Konkuk University, 1 Hwayang-Dong, Gwangjin-Gu, Seoul, Korea.
authors.forename: Hanna
authors.initials: H
authors.lastname: Lee
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Ham
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Jae-Hwan
authors.initials: JH
authors.lastname: Kim
authors.forename: Kyung Shin
authors.initials: KS
authors.lastname: Paek
authors.forename: Eun Sil
authors.initials: ES
authors.lastname: Kang
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jung Seok
authors.initials: JS
authors.lastname: Hwang
authors.forename: Taesik
authors.initials: T
authors.lastname: Yoo
authors.forename: Chankyu
authors.initials: C
authors.lastname: Park
authors.forename: Jin-Hoi
authors.initials: JH
authors.lastname: Kim
authors.forename: Dae-Seog
authors.initials: DS
authors.lastname: Lim
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 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C425931:GW 501516; D047495:PPAR gamma; D000081082:Phosphoinositide-3 Kinase Inhibitors; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; D013844:Thiazoles; D000804:Angiotensin II; D019255:NADPH Oxidases; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein