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PPARalpha inhibits ...
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Kintscher, Ulrich
(författare)
PPARalpha inhibits TGF-beta-induced beta5 integrin transcription in vascular smooth muscle cells by interacting with Smad4
- Artikel/kapitelEngelska2002
Förlag, utgivningsår, omfång ...
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:uu-10443
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-10443URI
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https://doi.org/10.1161/01.RES.0000046017.96083.34DOI
Kompletterande språkuppgifter
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Språk:engelska
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Sammanfattning på:engelska
Ingår i deldatabas
Klassifikation
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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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-beta (TGF-beta) is highly expressed in restenotic and atherosclerotic lesions, and known to induce integrin expression. Peroxisome proliferator-activated receptor alpha (PPARalpha), a member of the nuclear receptor superfamily, regulates gene expression in a variety of vascular cells. We investigated the effects of PPARalpha ligands on TGF-beta-induced beta3 and beta5 integrin expression and potential interaction between PPARalpha and TGF-beta signaling. PPARalpha ligands WY-14643 (100 micromol/L) and 5,8,11,14-eicosatetranoic acid (ETYA, 50 micromol/L) inhibited TGF-beta-induced beta5 integrin protein expression by 72+/-6.8% and 73+/-7.1%, respectively (both P<0.05). TGF-beta-stimulated beta3 integrin expression was not affected by PPARalpha ligands. Both PPARalpha ligands also suppressed TGF-beta-induced beta5 integrin mRNA levels. PPARalpha ligands inhibited TGF-beta-inducible transcription of beta5 integrin by an interaction with a TGF-beta response element between nucleotides -63 and -44, which contains a Sp1/Sp3 transcription factor binding site. Nuclear complexes binding to the TGF-beta response region contained Sp1/Sp3 and TGF-beta-regulated Smad 2, 3, and 4 transcription factors. TGF-beta-stimulated Sp1/Smad4 nuclear complex formation was inhibited by WY-14643 and ETYA with a parallel induction of PPARalpha/Smad4 interactions. However, in vitro pull-down experiments failed to demonstrate direct binding between PPARalpha/Smad4. Both PPARalpha ligands blocked PDGF-directed migration of TGF-beta-pretreated VSMCs, a process mediated, in part, by beta5 integrins. The present study demonstrates that PPARalpha activators inhibit TGF-beta-induced beta5 integrin transcription in VSMCs through a novel indirect interaction between ligand-activated PPARalpha and the TGF-beta-regulated Smad4 transcription factors.
Ämnesord och genrebeteckningar
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5;8;11;14-Eicosatetraynoic Acid/pharmacology
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Animals
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Cell Movement/drug effects
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Cells; Cultured
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DNA-Binding Proteins/*metabolism
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Gene Expression/drug effects
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Genes; Reporter
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Integrin beta Chains/*biosynthesis/genetics
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Integrin beta3/biosynthesis/genetics
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Ligands
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Macromolecular Substances
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Muscle; Smooth; Vascular/cytology/drug effects/*metabolism
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Nuclear Proteins/metabolism
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Platelet-Derived Growth Factor/pharmacology
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Promoter Regions (Genetics)/genetics
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Protein Binding/drug effects/physiology
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Pyrimidines/pharmacology
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RNA; Messenger/metabolism
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Rats
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Rats; Sprague-Dawley
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Receptors; Cytoplasmic and Nuclear
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Signal Transduction/drug effects/physiology
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Smad4 Protein
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Trans-Activators/*metabolism
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Transcription Factors/*pharmacology
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Transcription; Genetic/*drug effects
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Transforming Growth Factor beta/*pharmacology
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Lyon, Christopher
(författare)
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Wakino, Shu
(författare)
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Bruemmer, Dennis
(författare)
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Feng, Xu
(författare)
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Goetze, Stephan
(författare)
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Graf, Kristof
(författare)
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Moustakas, AristidisUppsala universitet,Ludwiginstitutet för cancerforskning(Swepub:uu)arimo287
(författare)
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Staels, Bart
(författare)
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Fleck, Eckart
(författare)
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Hsueh, Willa A.
(författare)
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Law, Ronald E.
(författare)
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Uppsala universitetLudwiginstitutet för cancerforskning
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Circulation Research91:11, s. e35-e440009-73301524-4571
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Till lärosätets databas
- Av författaren/redakt...
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Kintscher, Ulric ...
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Lyon, Christophe ...
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Wakino, Shu
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Bruemmer, Dennis
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Feng, Xu
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Goetze, Stephan
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visa fler...
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Graf, Kristof
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Moustakas, Arist ...
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Staels, Bart
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Fleck, Eckart
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Hsueh, Willa A.
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Law, Ronald E.
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visa färre...
- Artiklar i publikationen
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Circulation Rese ...
- Av lärosätet
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Uppsala universitet