Transforming growth factor-beta1 is a molecular target for the peroxisome proliferator-activated receptor delta.
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.
Kim
Hyo Jung
HJ
Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea.
Ham
Sun Ah
SA
Kim
Sung Uk
SU
Hwang
Jin-Yong
JY
Kim
Jae-Hwan
JH
Chang
Ki Churl
KC
Yabe-Nishimura
Chihiro
C
Kim
Jin-Hoi
JH
Seo
Han Geuk
HG
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
C425931:GW 501516; D008024:Ligands; D047494:PPAR delta; D012333:RNA, Messenger; D013844:Thiazoles; D053773:Transforming Growth Factor beta1