PPAR Inhibits TGF- –Induced 5 Integrin Transcription in Vascular Smooth Muscle Cells by Interacting With Smad4

Integrins play an important role in vascular smooth muscle cell (VSMC) migration, a crucial event in the development of restenosis and atherosclerosis. Transforming growth factor(TGF) is highly expressed in restenotic and atherosclerotic lesions, and known to induce integrin expression. Peroxisome proliferator-activated receptor (PPAR ), a member of the nuclear receptor superfamily, regulates gene expression in a variety of vascular cells. We investigated the effects of PPAR ligands on TGF–induced 3 and 5 integrin expression and potential interaction between PPAR and TGFsignaling. PPAR ligands WY-14643 (100 mol/L) and 5,8,11,14-eicosatetranoic acid (ETYA, 50 mol/L) inhibited TGF–induced 5 integrin protein expression by 72 6.8% and 73 7.1%, respectively (both P 0.05). TGF–stimulated 3 integrin expression was not affected by PPAR ligands. Both PPAR ligands also suppressed TGF–induced 5 integrin mRNA levels. PPAR ligands inhibited TGF–inducible transcription of 5 integrin by an interaction with a TGFresponse element between nucleotides 63 and 44, which contains a Sp1/Sp3 transcription factor binding site. Nuclear complexes binding to the TGFresponse region contained Sp1/Sp3 and TGF–regulated Smad 2, 3, and 4 transcription factors. TGF–stimulated Sp1/Smad4 nuclear complex formation was inhibited by WY-14643 and ETYA with a parallel induction of PPAR /Smad4 interactions. However, in vitro pull-down experiments failed to demonstrate direct binding between PPAR /Smad4. Both PPAR ligands blocked PDGF-directed migration of TGF–pretreated VSMCs, a process mediated, in part, by 5 integrins. The present study demonstrates that PPAR activators inhibit TGF–induced 5 integrin transcription in VSMCs through a novel indirect interaction between ligand-activated PPAR and the TGF–regulated Smad4 transcription factors. The full text of this article is available at http://www.circresaha.org. (Circ Res. 2002;91:e35-e44.)