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(Circulation Research. 2008;102:193.)
© 2008 American Heart Association, Inc.

Molecular Medicine

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

Hyo Jung Kim, Sun Ah Ham, Sung Uk Kim, Jin-Yong Hwang, Jae-Hwan Kim, Ki Churl Chang, Chihiro Yabe-Nishimura, Jin-Hoi Kim, Han Geuk Seo

From the Department of Pharmacology (H.J.K., S.A.H., K.C.C., H.G.S.) and Internal Medicine (S.U.K., J.-Y.H.), Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Korea; Graduate School of Life Science & Biotechnology (Jae-Hwan Kim), Pochon CHA University, Seoul, Korea; Department of Pharmacology (C.Y.-N.), Kyoto Prefectural University of Medicine, Japan; and Department of Animal Biotechnology (Jin-Hoi Kim), Kon-Kuk University, Seoul, Korea.

Correspondence to Han Geuk Seo, Department of Pharmacology, Gyeongsang National University School of Medicine, 92 Chilam-Dong, Jinju 660-751, Korea. E-mail hgseo{at}gnu.ac.kr

The peroxisome proliferator-activated receptor (PPAR) 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 PPAR target in VSMCs. The PPAR 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 PPAR or GW9662, an inhibitor of PPAR. Furthermore, activated PPAR 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 PPAR binding, which suggests that this site is a novel type of PPAR response element. In addition, ligand-activated PPAR 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 PPAR, anti–TGF-β1 antibody, or a TGF-β type I receptor inhibitor. Decreased monocyte chemoattractant protein-1 expression induced by PPAR 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 PPAR.

Key Words: monocyte chemoattractant protein-1 • peroxisome proliferator-activated receptor • transforming growth factor-β1 • vascular smooth muscle cells

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