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Research ArticleArticle

Endothelin-1 Is Induced by Cytokines in Human Vascular Smooth Muscle Cells: Evidence for Intracellular Endothelin-Converting Enzyme

Mandy Woods, Jane A. Mitchell, Elizabeth G. Wood, Stewart Barker, Nicholas R. Walcot, Gareth M. Rees and Timothy D. Warner
Molecular Pharmacology May 1999, 55 (5) 902-909;
Mandy Woods
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Jane A. Mitchell
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Elizabeth G. Wood
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Stewart Barker
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Nicholas R. Walcot
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Gareth M. Rees
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Timothy D. Warner
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Abstract

Endothelin-1 (ET-1) is the predominant endothelin isopeptide generated by the vascular wall and therefore appears to be the most important peptide involved in regulation of cardiovascular events. Many pathologic conditions are associated with elevations of ET-1 in the blood vessel wall. Because these conditions are often cytokine driven, we examined the effects of a mixture of cytokines on ET-1 production in human vascular smooth muscle cells (VSMCs) derived from internal mammary artery and saphenous vein (SV). Incubation of IMA and SV VSMCs with tumor necrosis factor-α (10 ng/ml) and interferon-γ (1000 U/ml) in combination for up to 48 h markedly elevated the expression of mRNA for prepro-ET-1 and the release of ET-1 into the culture medium. This cytokine-stimulated release of ET-1 was inhibited by a series of dual endothelin-converting enzyme (ECE)/neutral endopeptidase inhibitors, phosphoramidon, CGS 26303, and CGS 26393, with an accompanying increase in big ET-1 release but with no effect on expression of mRNA for prepro-ET-1. These same compounds were 10 times more potent at inhibiting the conversion of exogenously applied big ET-1 to ET-1. ECE-1b/c mRNA is present in SV VSMCs, however no ECE-1a is present in these cells. Thus VSMCs most probably contain, like endothelial cells, an intracellular ECE responsible for the endogenous synthesis of ET-1. Under the influence of pro-inflammatory mediators the vascular smooth muscle can therefore become an important site of ET-1 production, as has already been established for the dilator mediators nitric oxide, prostaglandin I2, and prostaglandin E2.

Footnotes

  • Send reprint requests to: Dr. Timothy D. Warner, Vascular Inflammation, The William Harvey Research Institute, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, United Kingdom. E-mail:t.d.warner{at}mds.qmw.ac.uk

  • M. W. was in receipt of a European Commission Training and Mobility Fellowship, N. R. W. holds an Aelwyn Bursary from the Joint Research Board of St. Bartholomew’s and the Royal London School of Medicine and Dentistry, J. A. M. is a Wellcome Foundation Career Development fellow, and T. D. W. is a British Heart Foundation Lecturer (BS/95003). Citation of meeting abstracts in which this work was previously presented: Woods M, Bishop-Bailey D, Pepper JR, Evans TW, Mitchell JA and Warner TD (1997) Cytokine and lipopolysaccharide stimulation of endothelin-1 release from internal mammary artery and saphenous vein smooth muscle cells.Br J Pharmacol122:18P; and Woods M, Wood EG, Mitchell JA and Warner TD (1998) Evidence for intracellular endothelin converting enzyme in human vascular smooth muscle cells.FASEB J12:A384.

  • Abbreviations:
    Big ET-1
    big endothelin-1
    ECE
    endothelin-converting enzyme
    ET-1
    endothelin-1
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    iNOS
    inducible nitric oxide synthase
    IFN-γ
    interferon-γ
    IMA
    internal mammary artery
    NEP
    neutral endopeptidase
    NO
    nitric oxide
    PGI2/E2
    prostaglandin I2/E2
    RT-PCR
    reverse transcription-polymerase chain reaction
    SV
    saphenous vein
    TNF-α
    tumor necrosis factor-α
    VSMCs
    vascular smooth muscle cells
    • Received November 4, 1998.
    • Accepted February 18, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (5)
Molecular Pharmacology
Vol. 55, Issue 5
1 May 1999
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Research ArticleArticle

Endothelin-1 Is Induced by Cytokines in Human Vascular Smooth Muscle Cells: Evidence for Intracellular Endothelin-Converting Enzyme

Mandy Woods, Jane A. Mitchell, Elizabeth G. Wood, Stewart Barker, Nicholas R. Walcot, Gareth M. Rees and Timothy D. Warner
Molecular Pharmacology May 1, 1999, 55 (5) 902-909;

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Research ArticleArticle

Endothelin-1 Is Induced by Cytokines in Human Vascular Smooth Muscle Cells: Evidence for Intracellular Endothelin-Converting Enzyme

Mandy Woods, Jane A. Mitchell, Elizabeth G. Wood, Stewart Barker, Nicholas R. Walcot, Gareth M. Rees and Timothy D. Warner
Molecular Pharmacology May 1, 1999, 55 (5) 902-909;
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