title: Transforming growth factor-beta1 is a molecular target for the peroxisome proliferator-activated receptor delta.
abstract: The peroxisome proliferator-activated receptor (PPAR)delta has been implicated in the pathogenesis of atherogenic disorders. However, its physiological roles and functions in vascular smooth muscle cells (VSMCs) remain relatively unclear. In the present study, we show that the gene encoding transforming growth factor (TGF)-beta1 is a PPARdelta target in VSMCs. The PPARdelta activator GW501516 upregulates TGF-beta1 expression in a dose- and time-dependent manner. This induction is attenuated significantly by the presence of small interfering RNA against PPARdelta or GW9662, an inhibitor of PPARdelta. Furthermore, activated PPARdelta induces TGF-beta1 promoter activity by binding to the direct repeat-1 response element TGF-beta1-direct repeat-1. Mutations in the 5' or 3' half-sites of the response element totally abrogate transcriptional activation and PPARdelta binding, which suggests that this site is a novel type of PPARdelta response element. In addition, ligand-activated PPARdelta attenuated the promoter activity and expression of monocyte chemoattractant protein-1 induced by interleukin-1beta. These effects were significantly reduced in the presence of small interfering RNA against PPARdelta, anti-TGF-beta1 antibody, or a TGF-beta type I receptor inhibitor. Decreased monocyte chemoattractant protein-1 expression induced by PPARdelta was mediated by the effector of TGF-beta1, Smad3. Finally, administration of GW501516 to mice upregulated TGF-beta1, whereas the expression of proinflammatory genes including monocyte chemoattractant protein-1 was significantly attenuated in the thoracic aorta. Taken together, these results demonstrate the presence of a novel TGF-beta1-mediated pathway in the antiinflammatory activities of PPARdelta.
authors.affiliation: Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Ham
authors.forename: Sung Uk
authors.initials: SU
authors.lastname: Kim
authors.forename: Jin-Yong
authors.initials: JY
authors.lastname: Hwang
authors.forename: Jae-Hwan
authors.initials: JH
authors.lastname: Kim
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yabe-Nishimura
authors.forename: Jin-Hoi
authors.initials: JH
authors.lastname: Kim
authors.forename: Han Geuk
authors.initials: HG
authors.lastname: Seo
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000473:pathology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation; D008024:Ligands; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D047494:PPAR delta / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger; D051381:Rats; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C425931:GW 501516; D008024:Ligands; D047494:PPAR delta; D012333:RNA, Messenger; D013844:Thiazoles; D053773:Transforming Growth Factor beta1