Transforming Growth Factor-β1 Is a Molecular Target for the Peroxisome Proliferator-Activated Receptor δ

Abstract

The peroxisome proliferator-activated receptor (PPAR)δ 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)-β1 is a PPARδ target in VSMCs. The PPARδ activator GW501516 upregulates TGF-β1 expression in a dose- and time-dependent manner. This induction is attenuated significantly by the presence of small interfering RNA against PPARδ or GW9662, an inhibitor of PPARδ. Furthermore, activated PPARδ induces TGF-β1 promoter activity by binding to the direct repeat-1 response element TGF-β1–direct repeat-1. Mutations in the 5′ or 3′ half-sites of the response element totally abrogate transcriptional activation and PPARδ binding, which suggests that this site is a novel type of PPARδ response element. In addition, ligand-activated PPARδ attenuated the promoter activity and expression of monocyte chemoattractant protein-1 induced by interleukin-1β. These effects were significantly reduced in the presence of small interfering RNA against PPARδ, anti–TGF-β1 antibody, or a TGF-β type I receptor inhibitor. Decreased monocyte chemoattractant protein-1 expression induced by PPARδ was mediated by the effector of TGF-β1, Smad3. Finally, administration of GW501516 to mice upregulated TGF-β1, 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-β1–mediated pathway in the antiinflammatory activities of PPARδ.