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Molecular Pharmacology

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Research ArticleArticle

α1D-Adrenergic Receptors and Mitogen-Activated Protein Kinase Mediate Increased Protein Synthesis by Arterial Smooth Muscle

Xiaohua Xin, Nengyu Yang, Andrea D. Eckhart and James E. Faber
Molecular Pharmacology May 1997, 51 (5) 764-775; DOI: https://doi.org/10.1124/mol.51.5.764
Xiaohua Xin
Department of Physiology, University of North Carolina, Chapel Hill, North Carolina 27599-7545
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Nengyu Yang
Department of Physiology, University of North Carolina, Chapel Hill, North Carolina 27599-7545
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Andrea D. Eckhart
Department of Physiology, University of North Carolina, Chapel Hill, North Carolina 27599-7545
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James E. Faber
Department of Physiology, University of North Carolina, Chapel Hill, North Carolina 27599-7545
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Abstract

Catecholamines may influence vascular smooth muscle cell (SMC) growth and vascular hypertrophic diseases. We previously demonstrated that stimulation of α1-adrenoceptors (AR) causes hypertrophy of vascular SMCs in vitro and in situ. Here, we used adult rat aorta SMCs that express α1D- and α1B-ARs (but not α1A-ARs) in vitro to examine the mechanisms and α1-AR subtypes involved. Norepinephrine (NE) increased protein synthesis and content in a time- and dose-dependent manner. To identify the responsible α1-AR subtype, we first documented the selectivity of two α1-AR subtype antagonists, BMY 7378 (α1D-AR antagonist) and chloroethylclonidine (CEC; α1B-AR antagonist), using Rat-1 fibroblasts stably transfected with the three different rodent α1-AR cDNAs. NE dose-dependently increased protein synthesis in each cell line. In α1D fibroblasts, BMY 7378 inhibited growth and protected α1D-ARs from CEC alkylation while having little blocking or protecting effect on the growth induced by stimulation of fibroblasts that express α1A- or α1B-ARs. In rat aorta SMCs, pretreatment with CEC in the presence of BMY 7378 to protect α1D-ARs had no effect on NE-induced protein synthesis. BMY 7378 inhibited the SMC growth response with a pK b of 8.4. NE caused rapid and transient p42-p44 mitogen-activated protein kinase (MAPK) activation that was α1D-AR dependent. Furthermore, NE caused tyrosine phosphorylation of multiple cellular proteins, phosphorylation of Raf-1, and stimulation of c-fos mRNA expression in aorta SMCs. The selective MAPK kinase inhibitor PD 98059 inhibited NE-induced protein synthesis and MAPK activation with IC50values of 2.3 and 1.6 μm, respectively. These data demonstrate that SMC growth induced by NE is mediated by α1D-ARs that couple to activation of the MAPK cascade.

Footnotes

    • Received December 2, 1996.
    • Accepted January 28, 1997.
  • Send reprint requests to: Dr. James E. Faber, Department of Physiology, 474 MSRB, 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 American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 51 (5)
Molecular Pharmacology
Vol. 51, Issue 5
1 May 1997
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Research ArticleArticle

α1D-Adrenergic Receptors and Mitogen-Activated Protein Kinase Mediate Increased Protein Synthesis by Arterial Smooth Muscle

Xiaohua Xin, Nengyu Yang, Andrea D. Eckhart and James E. Faber
Molecular Pharmacology May 1, 1997, 51 (5) 764-775; DOI: https://doi.org/10.1124/mol.51.5.764

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Research ArticleArticle

α1D-Adrenergic Receptors and Mitogen-Activated Protein Kinase Mediate Increased Protein Synthesis by Arterial Smooth Muscle

Xiaohua Xin, Nengyu Yang, Andrea D. Eckhart and James E. Faber
Molecular Pharmacology May 1, 1997, 51 (5) 764-775; DOI: https://doi.org/10.1124/mol.51.5.764
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