Published online before print November 7, 2002, doi: 10.1161/01.RES.0000046017.96083.34
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Submitted on July 12, 2001
Revised on October 16, 2002
Accepted on October 29, 2002
PPAR
Inhibits TGF-
-Induced 5 Integrin Transcription in Vascular Smooth Muscle Cells by Interacting With Smad4
Ulrich Kintscher ;
From the Department of Medicine (U.K., C.L., S.W., D.B., W.A.H., R.E.L.), Division of Endocrinology, Diabetes and Hypertension, University of California, Los Angeles, School of Medicine, Los Angeles, Calif; Institute of Pharmacology and Toxicology (U.K.), Charité Hospital, Humboldt-University Berlin, Berlin, Germany; the Department of Medicine/Cardiology (D.B., S.G., K.G., E.F.), German Heart Institute Berlin, Berlin, Germany; the Department of Pathology (X.F.), University of Alabama, Birmingham, Ala; Ludwig Institute for Cancer Research (A.M.), Uppsala, Sweden; the Department d'Atherosclerose (B.S.), UR545 INSERM, Institut Pasteur de Lille and Faculté de Pharmacie, Universitè de Lille II, Lille, France.
* To whom correspondence should be addressed. E-mail: rlaw{at}mednet.ucla.edu.
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 TGF- signaling. PPAR ligands WY-14643 (100 µmol/L) and 5,8,11,14-eicosatetranoic acid (ETYA, 50 µmol/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 TGF- response element between nucleotides -63 and -44, which contains a Sp1/Sp3 transcription factor binding site. Nuclear complexes binding to the TGF- response 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.
Key words: peroxisome proliferator-activated receptor
•
integrin •
transforming growth factor- •
vascular smooth muscle cell
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