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(Circulation Research. 2002;91:e35.)
© 2002 American Heart Association, Inc.

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PPAR Inhibits TGF-ß–Induced ß₅ Integrin Transcription in Vascular Smooth Muscle Cells by Interacting With Smad4

Ulrich Kintscher, Christopher Lyon, Shu Wakino, Dennis Bruemmer, Xu Feng, Stephan Goetze, Kristof Graf, Aristidis Moustakas, Bart Staels, Eckart Fleck, Willa A. Hsueh, Ronald E. Law

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.

Correspondence to Ronald E. Law, PhD, UCLA School of Medicine, Division of Endocrinology, Diabetes and Hypertension, Warren Hall, Second Floor, Suite 24-130, 900 Veteran Ave, Box 957073, Los Angeles, CA 90095. 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-ß (TGF-ß) 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-ß–induced ß₃ and ß₅ integrin expression and potential interaction between PPAR and TGF-ß signaling. PPAR ligands WY-14643 (100 µmol/L) and 5,8,11,14-eicosatetranoic acid (ETYA, 50 µmol/L) inhibited TGF-ß–induced ß₅ integrin protein expression by 72±6.8% and 73±7.1%, respectively (both P<0.05). TGF-ß–stimulated ß₃ integrin expression was not affected by PPAR ligands. Both PPAR ligands also suppressed TGF-ß–induced ß₅ integrin mRNA levels. PPAR ligands inhibited TGF-ß–inducible transcription of ß₅ integrin by an interaction with a TGF-ß response element between nucleotides -63 and -44, which contains a Sp1/Sp3 transcription factor binding site. Nuclear complexes binding to the TGF-ß response region contained Sp1/Sp3 and TGF-ß–regulated Smad 2, 3, and 4 transcription factors. TGF-ß–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-ß–pretreated VSMCs, a process mediated, in part, by ß₅ integrins. The present study demonstrates that PPAR activators inhibit TGF-ß–induced ß₅ integrin transcription in VSMCs through a novel indirect interaction between ligand-activated PPAR and the TGF-ß–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-ß • vascular smooth muscle cell

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