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Endothelin-1 activates ETA receptors on human vascular smooth muscle cells to yield proteoglycans with increased binding to LDL

  • Author Footnotes
    1 These authors contributed equally to this work.
    Mandy L. Ballinger
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Diabetes and Cell Biology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Melanie E. Ivey
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Diabetes and Cell Biology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia

    Departments of Medicine, Central and Eastern Clinical School, Alfred Hospital, Monash University, Melbourne, Victoria 3004, Australia
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  • Narin Osman
    Affiliations
    Diabetes and Cell Biology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia

    Departments of Medicine, Central and Eastern Clinical School, Alfred Hospital, Monash University, Melbourne, Victoria 3004, Australia

    Immunology, Central and Eastern Clinical School, Alfred Hospital, Monash University, Melbourne, Victoria 3004, Australia
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  • Walter G. Thomas
    Affiliations
    School of Biomedical Sciences, The University of Queensland, Brisbane 4072, Australia
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  • Peter J. Little
    Correspondence
    Corresponding author at: Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, Australia. Tel.: +61 3 8532 1203; fax: +61 3 8535 1100.
    Affiliations
    Diabetes and Cell Biology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia

    Departments of Medicine, Central and Eastern Clinical School, Alfred Hospital, Monash University, Melbourne, Victoria 3004, Australia

    Immunology, Central and Eastern Clinical School, Alfred Hospital, Monash University, Melbourne, Victoria 3004, Australia
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Abstract

      Objective

      Lipid retention in the vessel wall by glycosaminoglycan (GAG) chains on chondroitin/dermatan sulfate proteoglycans synthesized by vascular smooth muscle cells (VSMC) have recently been established as an early event in human coronary artery atherosclerosis. GAG structure can be altered by growth factors resulting in enhanced binding to low density lipoprotein (LDL). The aim of this study was to determine if proteoglycans produced by endothelin-1 treated VSMCs had increased binding to human LDL, to examine the effect of endothelin-1 on the synthesis and structure of proteoglycans and to elucidate the signalling pathway.

      Methods and results

      Endothelin-1 stimulated an increase in [35S]sulfate and [3H]glucosamine incorporation into proteoglycans produced by human VSMC. The increase was due to an increase in GAG chain size assessed by SDS-PAGE and size exclusion chromatography. Increased radiolabel incorporation was inhibited by an ETA but not an ETB receptor antagonist. Endothelin-1 stimulated an increase in the 6:4 position sulfation ratio on the disaccharides of the GAG chains, an effect that was blocked by bosentan. The EGF receptor antagonist AG1478 did not affect the increase in GAG size mediated by endothelin-1. Inhibition of protein kinase C (PKC) with GF109203X or down regulation by PMA pre-treatment attenuated the effect of endothelin-1 on GAG synthesis.

      Conclusion

      These data demonstrate that endothelin-1 stimulates changes in GAG chain structure that increase binding to LDL. This action of endothelin-1 may represent a new target for the prevention of lipid binding within the vascular wall and the associated complications resulting from this interaction.

      Keywords

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