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

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

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