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Sökning: WFRF:(Lyon Christopher) > (2002-2004) > PPARalpha inhibits ...

  • 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 ...

  • 2002
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-10443
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-10443URI
  • https://doi.org/10.1161/01.RES.0000046017.96083.34DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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

  • 5;8;11;14-Eicosatetraynoic Acid/pharmacology
  • Animals
  • Cell Movement/drug effects
  • Cells; Cultured
  • DNA-Binding Proteins/*metabolism
  • Gene Expression/drug effects
  • Genes; Reporter
  • Integrin beta Chains/*biosynthesis/genetics
  • Integrin beta3/biosynthesis/genetics
  • Ligands
  • Macromolecular Substances
  • Muscle; Smooth; Vascular/cytology/drug effects/*metabolism
  • Nuclear Proteins/metabolism
  • Platelet-Derived Growth Factor/pharmacology
  • Promoter Regions (Genetics)/genetics
  • Protein Binding/drug effects/physiology
  • Pyrimidines/pharmacology
  • RNA; Messenger/metabolism
  • Rats
  • Rats; Sprague-Dawley
  • Receptors; Cytoplasmic and Nuclear
  • Signal Transduction/drug effects/physiology
  • Smad4 Protein
  • Trans-Activators/*metabolism
  • Transcription Factors/*pharmacology
  • Transcription; Genetic/*drug effects
  • Transforming Growth Factor beta/*pharmacology

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Lyon, Christopher (författare)
  • Wakino, Shu (författare)
  • Bruemmer, Dennis (författare)
  • Feng, Xu (författare)
  • Goetze, Stephan (författare)
  • Graf, Kristof (författare)
  • Moustakas, AristidisUppsala universitet,Ludwiginstitutet för cancerforskning(Swepub:uu)arimo287 (författare)
  • Staels, Bart (författare)
  • Fleck, Eckart (författare)
  • Hsueh, Willa A. (författare)
  • Law, Ronald E. (författare)
  • Uppsala universitetLudwiginstitutet för cancerforskning (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Circulation Research91:11, s. e35-e440009-73301524-4571

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