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In vivo suppression of restenosis in balloon-injured rat carotid artery by adenovirus-mediated gene transfer of the cell surface-directed plasmin inhibitor ATF.BPTI

Gene Therapy volume 8, pages 534–541 (2001)Cite this article

Abstract

Injury-induced neointimal development results from migration and proliferation of vascular smooth muscle cells (SMC). Cell migration requires controlled proteolytic degradation of extracellular matrix surrounding the cell. Plasmin is a major contributor to this process by degrading various matrix proteins directly, or indirectly by activating matrix metalloproteinases. This makes it an attractive target for inhibition by gene transfer. An adenoviral vector, Ad.ATF.BPTI, was constructed encoding a hybrid protein, which consists of the aminoterminal fragment (ATF) of urokinase-type plasminogen activator (u-PA) linked to bovine pancreas trypsin inhibitor (BPTI), a potent inhibitor of plasmin. This hybrid protein binds to the u-PA receptor, thereby inhibiting plasmin activity at the cell surface, and was found to be a potent inhibitor of cell migration in vitro. Local infection with Ad.ATF.BPTI of balloon-injured rat carotid artery resulted in detectable expression of ATF.BPTI mRNA and protein in the vessel wall. Morphometric analysis of arterial cross-sections revealed that delivery of Ad.ATF.BPTI to the carotid artery wall at the time of balloon injury inhibited neointima formation by 53% (P < 0.01) at 14 days and 19% (P = NS) at 28 days after injury when compared with control vector-infected arteries. Intima/media ratios were decreased by 60% (P < 0.01) and 35% (P < 0.05) at 14 and 28 days, respectively, when compared with control vector-infected arteries. Furthermore, a small but significant increase in medial area was found in the Ad.ATF.BPTI-treated arteries at 28 days (P < 0.05). These results show that local infection of the vessel wall with Ad.ATF.BPTI reduces neointima formation, presumably by inhibiting SMC migration, thereby offering a novel therapeutic approach to inhibiting neointima development.

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Acknowledgements

We would like to thank Erik Offerman for technical assistance. This study is supported by the Netherlands Heart Foundation, grants 95–126 and M93–001.

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Author notes

  1. M L M Lamfers and J H P Lardenoye: MLM Lamfers and JHP Lardenoye contributed equally

Authors and Affiliations

  1. Gaubius Laboratory TNO-PG, Leiden, The Netherlands

    M L M Lamfers, J H P Lardenoye, M R de Vries, M C Aalders, J M Grimbergen, V W M van Hinsbergh & P H A Quax

  2. Department of Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands

    M A Engelse

  3. Department of Physiology, Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands

    V W M van Hinsbergh

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Lamfers, M., Lardenoye, J., de Vries, M. et al. In vivo suppression of restenosis in balloon-injured rat carotid artery by adenovirus-mediated gene transfer of the cell surface-directed plasmin inhibitor ATF.BPTI. Gene Ther 8, 534–541 (2001). https://doi.org/10.1038/sj.gt.3301437

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