Print Email Facebook Twitter Gene transfer of the urokinase-type plasminogen activator receptor-targeted matrix metalloproteinase inhibitor TIMP-1.ATF suppresses neointima formation more efficiently than tissue inhibitor of metalloproteinase-1 Title Gene transfer of the urokinase-type plasminogen activator receptor-targeted matrix metalloproteinase inhibitor TIMP-1.ATF suppresses neointima formation more efficiently than tissue inhibitor of metalloproteinase-1 Author Lamfers, M.L.M. Grimbergen, J.M. Aalders, M.C. Havenga, M.J. de Vries, M.R. Huisman, L.G.M. van Hinsbergh, V.W.M. Quax, P.H.A. Gaubius instituut TNO Publication year 2002 Abstract Proteases of the plasminogen activator (PA) and matrix metalloproteinase (MMP) system play an important role in smooth muscle cell (SMC) migration and neointima formation after vascular injury. Inhibition of either PAs or MMPs has previously been shown to result in decreased neointima formation in vivo. To inhibit both protease systems simultaneously, a novel hybrid protein, TIMP-1.ATF, was constructed consisting of the tissue inhibitor of metalloproteinase-1 (TIMP-1) domain, as MMP inhibitor, linked to the receptor-binding amino terminal fragment (ATF) of urokinase. By binding to the u-PA receptor this protein will not only anchor the TIMP-1 moiety directly to the cell surface, it will also prevent the local activation of plasminogen by blocking the binding of urokinase-type plasminogen activator (u-PA) to its receptor. Adenoviral expression of TIMP-1.ATF was used to inhibit SMC migration and neointima formation in human saphenous vein segments in vitro. SMC migration was inhibited by 65% in Ad.TIMP-1.ATF-infected cells. Infection with adenoviral vectors encoding the individual domains, Ad.TIMP-1 and Ad.ATF, reduced migration by 32% and 52%, respectively. Neointima formation in saphenous vein organ cultures infected with Ad.TIMP-1.ATF was inhibited by 72% compared with 42% reduction after Ad.TIMP-1 infection and 34% after Ad.ATF infection. These data show that binding of TIMP-1.ATF hybrid protein to the u-PA receptor at the cell surface strongly enhances the inhibitory effect of TIMP-1 on neointima formation in human saphenous vein cultures. Subject BiologyAdenovirusMatrix metalloproteinasesNeointima formationPlasmin(ogen)Urokinase-type plasminogen activatorAdenovirusAdenoviridaeAnimalsCell DivisionCell MembraneCell MovementCells, CulturedCHO CellsCollagenasesCricetinaeCulture Media, ConditionedEnzyme ActivationFlow CytometryGene Transfer TechniquesHumansMatrix Metalloproteinase 13Muscle, Smooth, VascularProtein Structure, TertiaryReceptors, Cell SurfaceRecombinant Fusion ProteinsRNA, MessengerSaphenous VeinTissue Inhibitor of Metalloproteinase-1Tunica IntimaUrinary Plasminogen Activator To reference this document use: http://resolver.tudelft.nl/uuid:f9ac767f-bc83-43ba-be59-3d24d502363f DOI https://doi.org/10.1161/01.res.0000041418.51906.57 TNO identifier 236777 ISSN 0009-7330 Source Circulation Research, 91 (10), 945-952 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.