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Molecular Pharmacology

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Research ArticleArticle

Platelet-Derived Growth Factor-BB Inhibits Rat α1D-Adrenergic Receptor Gene Expression in Vascular Smooth Muscle Cells by Inducing AP-2-Like Protein Binding to α1D Proximal Promoter Region

Xiaohua Xin, Nengyu Yang and James E. Faber
Molecular Pharmacology December 1999, 56 (6) 1152-1161; DOI: https://doi.org/10.1124/mol.56.6.1152
Xiaohua Xin
Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
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Nengyu Yang
Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
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James E. Faber
Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
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Abstract

We have previously found that, in addition to mediating contraction of vascular smooth muscle, activation of α1D-adrenergic receptors (AR) induces smooth muscle cell (SMC) hypertrophy. Despite their importance, little is known about how α1D-AR expression is regulated. Recently, we demonstrated that platelet-derived growth factor (PDGF)-β receptor stimulation, but not various other growth factors, inhibits transcription of α1D-, but not α1A- or α1B-ARs, resulting in reduced norepinephrine-mediated SMC growth. To investigate this inhibitory mechanism, herein we cloned and characterized 1.6 kb of the 5′-flanking region of the rat α1D-AR gene. Reporter gene transfection assays in rat aorta and vena cava SMCs showed that this 5′-flanking region, which lacks a TATA-box, possesses strong promoter activity. Two transcription initiation sites and their flanking promotor regions were identified, wherein the proximal promotor mediated PDGF-BB inhibition of transcription. Gel mobility shift assays suggested that Sp1 binds constitutively at two consensus sites within the −399 base pair (bp)/−349-bp region of the proximal promotor. This constitutive binding was unaffected by PDGF-BB. In contrast, a flanking motif (−384 bp/−349 bp), possessing putative Sp1/activator protein-2 (AP-2) overlapping binding sites and located upstream of the proximal transcription initiation site, was required for PDGF-BB inhibition of α1D transcription. PDGF-BB increased AP-2 binding to the distal AP-2 site in this region in the context of SMCs. Furthermore, overexpression of AP-2 protein, by transgene transfection, dose-dependently inhibited α1D-AR activity driven by this motif. Thus, PDGF-BB may increase AP-2 binding within the proximal promoter to cause down-regulation of α1D-AR expression in SMCs when PDGF is elevated, such as in the postnatal growing vascular wall and in vascular hypertrophic diseases.

Footnotes

    • Received April 29, 1999.
    • Accepted August 24, 1999.
  • Send reprint requests to: James E Faber, Ph.D., Department of Cell and Molecular Physiology, 474MSRB, University of North Carolina, Chapel Hill, NC 27599-7545. E-mail: jefaber{at}med.unc.edu

  • This study was supported by National Institutes of Health Grant HL52610. The GenBank accession number for the α1D-adrenergic receptor promotor sequence reported herein is AF071014. Sequence scanning revealed no significant relatedness to other sequences except the α1D gene of other species.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (6)
Molecular Pharmacology
Vol. 56, Issue 6
1 Dec 1999
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Research ArticleArticle

Platelet-Derived Growth Factor-BB Inhibits Rat α1D-Adrenergic Receptor Gene Expression in Vascular Smooth Muscle Cells by Inducing AP-2-Like Protein Binding to α1D Proximal Promoter Region

Xiaohua Xin, Nengyu Yang and James E. Faber
Molecular Pharmacology December 1, 1999, 56 (6) 1152-1161; DOI: https://doi.org/10.1124/mol.56.6.1152

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Research ArticleArticle

Platelet-Derived Growth Factor-BB Inhibits Rat α1D-Adrenergic Receptor Gene Expression in Vascular Smooth Muscle Cells by Inducing AP-2-Like Protein Binding to α1D Proximal Promoter Region

Xiaohua Xin, Nengyu Yang and James E. Faber
Molecular Pharmacology December 1, 1999, 56 (6) 1152-1161; DOI: https://doi.org/10.1124/mol.56.6.1152
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