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Molecular Pharmacology

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Research ArticleArticle

Regulation of Human Vascular Protease-Activated Receptor-3 through mRNA Stabilization and the Transcription Factor Nuclear Factor of Activated T Cells (NFAT)

Anke C. Rosenkranz, Bernhard H. Rauch, Anke Doller, Wolfgang Eberhardt, Andreas Böhm, Ellen Bretschneider and Karsten Schrör
Molecular Pharmacology August 2011, 80 (2) 337-344; DOI: https://doi.org/10.1124/mol.111.072850
Anke C. Rosenkranz
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Bernhard H. Rauch
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Anke Doller
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Wolfgang Eberhardt
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Andreas Böhm
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Ellen Bretschneider
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Karsten Schrör
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Abstract

Thrombin promotes vascular smooth muscle cell (SMC) proliferation and inflammation via protease-activated receptor (PAR)-1. A further thrombin receptor, PAR-3, acts as a PAR-1 cofactor in some cell-types. Unlike PAR-1, PAR-3 is dynamically regulated at the mRNA level in thrombin-stimulated SMC. This study investigated the mechanisms controlling PAR-3 expression. In human vascular SMC, PAR-3 siRNA attenuated thrombin-stimulated interleukin-6 expression and extracellular signal-regulated kinases 1/2 phosphorylation, indicating PAR-3 contributes to net thrombin responses in these cells. Thrombin slowed the decay of PAR-3 but not PAR-1 mRNA in the presence of actinomycin D and induced cytosolic shuttling and PAR-3 mRNA binding of the mRNA-stabilizing protein human antigen R (HuR). HuR siRNA prevented thrombin-induced PAR-3 expression. By contrast, forskolin inhibited HuR shuttling and destabilized PAR-3 mRNA, thus reducing PAR-3 mRNA and protein expression. Other cAMP-elevating agents, including the prostacyclin-mimetic iloprost, also down-regulated PAR-3, accompanied by decreased HuR/PAR-3 mRNA binding. Iloprost-induced suppression of PAR-3 was reversed with a myristoylated inhibitor of protein kinase A and mimicked by phorbol ester, an inducer of cyclooxygenase-2. In separate studies, iloprost attenuated PAR-3 promoter activity and prevented binding of nuclear factor of activated T cells (NFAT2) to the human PAR-3 promoter in a chromatin immunoprecipitation assay. Accordingly, PAR-3 expression was suppressed by the NFAT inhibitor cyclosporine A or NFAT2 siRNA. Thus human PAR-3, unlike PAR-1, is regulated post-transcriptionally via the mRNA-stabilizing factor HuR, whereas transcriptional control involves NFAT2. Through modulation of PAR-3 expression, prostacyclin and NFAT inhibitors may limit proliferative and inflammatory responses to thrombin after vessel injury.

Footnotes

  • This study was supported in part by the Deutsche Forschungsgemeinschaft [SCH 194/11-10; SFB 612 Project B11], the Forschungskommission der Heinrich-Heine-Universität Düsseldorf [Grant 9772399]; the Ernst und Berta Grimmke-Stiftung [Grant 3/09]; and the Gesellschaft für Thrombose- und Hämostase- Forschung [Rudolf-Marx Stipend].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.072850.

  • ABBREVIATIONS:

    SMC
    smooth muscle cell
    CsA
    cyclosporin A
    EPAC
    exchange protein directly activated by cAMP
    ERK1/2
    extracellular-regulated kinase 1/2
    HuR
    human antigen R
    IBMX
    isobutyl-1-methylxanthine
    IL-6
    interleukin-6
    NFAT
    nuclear factor of activated T cells
    PAR
    protease-activated receptor
    PGI2
    prostacyclin
    PKA
    protein kinase A
    PKI
    myristoylated protein kinase A inhibitor
    PMA
    phorbol 12-myristate 13-acetate
    VASP
    vasodilator-stimulated phosphoprotein
    VSMC
    vascular smooth muscle cell
    ChIP
    chromatin immunoprecipitation
    PCR
    polymerase chain reaction
    UTR
    untranslated region
    IP
    immunoprecipitation
    siRNA
    short interfering RNA
    db-cAMP
    dibutyryl cAMP
    8CPT-2Me-cAMP
    8-(4-chlorophenylthio)-2′-O-methyl-cAMP, sodium salt
    COX-2
    cyclooxygenase-2.

  • Received April 8, 2011.
  • Accepted May 18, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (2)
Molecular Pharmacology
Vol. 80, Issue 2
1 Aug 2011
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Research ArticleArticle

Regulation of Human Vascular Protease-Activated Receptor-3 through mRNA Stabilization and the Transcription Factor Nuclear Factor of Activated T Cells (NFAT)

Anke C. Rosenkranz, Bernhard H. Rauch, Anke Doller, Wolfgang Eberhardt, Andreas Böhm, Ellen Bretschneider and Karsten Schrör
Molecular Pharmacology August 1, 2011, 80 (2) 337-344; DOI: https://doi.org/10.1124/mol.111.072850

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Research ArticleArticle

Regulation of Human Vascular Protease-Activated Receptor-3 through mRNA Stabilization and the Transcription Factor Nuclear Factor of Activated T Cells (NFAT)

Anke C. Rosenkranz, Bernhard H. Rauch, Anke Doller, Wolfgang Eberhardt, Andreas Böhm, Ellen Bretschneider and Karsten Schrör
Molecular Pharmacology August 1, 2011, 80 (2) 337-344; DOI: https://doi.org/10.1124/mol.111.072850
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