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Adenovirus-mediated gene transfer of fibromodulin inhibits neointimal hyperplasia in an organ culture model of human saphenous vein graft disease

Gene Therapy volume 16, pages 1154–1162 (2009)Cite this article

Abstract

Poor long-term graft patency remains a major limitation of coronary artery bypass grafting using saphenous vein aortocoronary grafts. Neointimal hyperplasia (NIH) represents the principal mechanism of graft failure; a substantial body of evidence implicates transforming growth factor-β1 (TGF-β1) in the pathogenesis of NIH. The small leucine-rich proteoglycans decorin and fibromodulin possess TGF-β-antagonist activity to differing extents and with differing avidities for the isoforms of TGF-β. We compared their ability to inhibit NIH in an ex vivo model of human saphenous vein organ culture following adenovirus-mediated gene transfer. Surgically prepared human saphenous vein segments received adenovirus expressing fibromodulin (Ad5-Fmod), decorin (Ad5-Dcn), β-galactosidase (Ad5-lacZ) or vehicle-only. Computerized morphometry 14 days after infection revealed significantly reduced neointimal area, neointimal thickness and intima/media ratio in Ad5-Fmod- and Ad5-Dcn-infected veins. Each parameter was significantly smaller in Ad5-Fmod- than in Ad5-Dcn-exposed segments. Fibrillar collagen content and levels of biologically active TGF-β were lower in vessels receiving Ad5-Fmod or Ad5-Dcn than in those receiving Ad5-lacZ or vehicle-only. Fibromodulin is a more potent inhibitor of NIH in cultured human saphenous vein than decorin and offers potential therapeutic benefits in saphenous vein graft failure (and possibly in other forms of accelerated atherosclerosis) by reduction of associated neointima formation.

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Acknowledgements

Dr Ranjzad was supported by a PhD studentship from the Iranian ministry of Health and Medical Education. Dr Kingston was a British Heart Foundation Intermediate Research Fellow (FS/04/026) during this work. Dr Salem was an MRC PhD student. Vein segments were provided from the cardiothoracic theatres of Manchester Royal infirmary.

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Author notes

  1. H K Salem

    Present address: 2Present address: Translational Cardiovascular Therapeutics, Barts and The London, Queen Mary's School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.,

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  1. Vascular Gene Therapy Unit, Research School of Clinical & Laboratory Sciences, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

    P Ranjzad, H K Salem & P A Kingston

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  1. P Ranjzad
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Correspondence to P A Kingston.

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Ranjzad, P., Salem, H. & Kingston, P. Adenovirus-mediated gene transfer of fibromodulin inhibits neointimal hyperplasia in an organ culture model of human saphenous vein graft disease. Gene Ther 16, 1154–1162 (2009). https://doi.org/10.1038/gt.2009.63

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