Published online before print October 10, 2002, doi: 10.1161/01.RES.0000041418.51906.57
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Submitted on June 29, 2000
Revised on October 2, 2002
Accepted on October 2, 2002
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
M. L.M. Lamfers ;
From the Gaubius Laboratory TNO-PG (M.L.M.L., J.M.G., M.C.A., M.R.d.V., L.G.M.H., V.W.M.v.H., P.H.A.Q.), Leiden, the Netherlands; Crucell Holland (M.J.H.), Leiden, the Netherlands; and Department of Physiology (V.W.M.v.H.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands.
* To whom correspondence should be addressed. E-mail: PHA.Quax{at}pg.tno.nl.
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.
Key words: neointima formation • matrix metalloproteinases • plasmin(ogen) • urokinase-type plasminogen activator • adenovirus
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