(Circulation. 2001;103:562.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Adenoviral Expression of a Urokinase Receptor–Targeted Protease Inhibitor Inhibits Neointima Formation in Murine and Human Blood Vessels
From the Gaubius Laboratory TNO-PG (P.H.A.Q., M.L.M.L., J.H.P.L., J.M.G., M.R.d.V, J.S., J.H.V., V.W.M.v.H.), and Department of Anatomy and Embryology, LUMC (M.C.d.R.), Leiden, and Department of Physiology, Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam (V.W.M.v.H.), Netherlands; and the Department of Pathology, AZ Middelheim, Antwerp, Belgium (M.M.K.).
Correspondence to Dr P.H.A. Quax, Gaubius Laboratory TNO-PG, PO Box 2215, 2301CE Leiden, Netherlands. E-mail pha.quax{at}pg.tno.nl
Background—Smooth
muscle cell migration, in addition to proliferation, contributes to a
large extent to the neointima formed in humans after balloon
angioplasty or bypass surgery. Plasminogen activator/plasmin–mediated
proteolysis is an important mediator of this smooth muscle cell
migration. Here, we report the construction of a novel hybrid protein
designed to inhibit the activity of cell surface–bound plasmin, which
cannot be inhibited by its natural inhibitors, such as
2-antiplasmin. This hybrid protein,
consisting of the receptor-binding amino-terminal fragment of uPA
(ATF), linked to the potent protease inhibitor bovine pancreas trypsin
inhibitor (BPTI), can inhibit plasmin activity at the cell
surface.
Methods and Results—The effect of adenovirus-mediated ATF.BPTI expression on neointima formation was tested in human saphenous vein organ cultures. Infection of human saphenous vein segments with Ad.CMV.ATF.BPTI (5x109 pfu/mL) resulted in 87.5±3.8% (mean±SEM, n=10) inhibition of neointima formation after 5 weeks, whereas Ad.CMV.ATF or Ad.CMV.BPTI virus had only minimal or no effect on neointima formation. The efficacy of ATF.BPTI in vivo was demonstrated in a murine model for neointima formation. Neointima formation in the femoral artery of mice, induced by placement of a polyethylene cuff, was strongly inhibited (93.9±2%) after infection with Ad.CMV.mATF.BPTI, a variant of ATF.BPTI able to bind specifically to murine uPA receptor; Ad.CMV.mATF and Ad.CMV.BPTI had no significant effect.
Conclusions—These data provide evidence that adenoviral transfer of a hybrid protein that binds selectively to the uPA receptor and inhibits plasmin activity directly on the cell surface is a powerful approach to inhibiting neointima formation and restenosis.
Key Words: plasminogen • restenosis • gene therapy • urokinase • receptors
This article has been cited by other articles:
 |
|
 |
|
  J. Wu, L. Peng, G. A. McMahon, D. A. Lawrence, and W. P. Fay Recombinant Plasminogen Activator Inhibitor-1 Inhibits Intimal Hyperplasia Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1565 - 1570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M M Pires, D. Eefting, M. R de Vries, P. H A Quax, and J W. Jukema Sirolimus and paclitaxel provoke different vascular pathological responses after local delivery in a murine model for restenosis on underlying atherosclerotic arteries Heart, August 1, 2007; 93(8): 922 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. P. Fay, N. Garg, and M. Sunkar Vascular Functions of the Plasminogen Activation System Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1231 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M.M. Pires, T. W.H. Pols, M. R. de Vries, C. M. van Tiel, P. I. Bonta, M. Vos, E. K. Arkenbout, H. Pannekoek, J. W. Jukema, P. H.A. Quax, et al. Activation of Nuclear Receptor Nur77 by 6-Mercaptopurine Protects Against Neointima Formation Circulation, January 30, 2007; 115(4): 493 - 500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. D. Krom, N. M.M. Pires, J. W. Jukema, M. R. de Vries, R. R. Frants, L. M. Havekes, K. W. van Dijk, and P. H.A. Quax Inhibition of neointima formation by local delivery of estrogen receptor alpha and beta specific agonists Cardiovasc Res, January 1, 2007; 73(1): 217 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. W.M. van Hinsbergh, M. A. Engelse, and P. H.A. Quax Pericellular Proteases in Angiogenesis and Vasculogenesis Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 716 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. M.M. Pires, A. Schepers, B. L. van der Hoeven, M. R. de Vries, L. S.M. Boesten, J. W. Jukema, and P. H.A. Quax Histopathologic alterations following local delivery of dexamethasone to inhibit restenosis in murine arteries Cardiovasc Res, December 1, 2005; 68(3): 415 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Monraats, J. S. Rana, M. C. Nierman, N. M.M. Pires, A. H. Zwinderman, J. J.P. Kastelein, J. A. Kuivenhoven, M. P.M. de Maat, S. Z.H. Rittersma, A. Schepers, et al. Lipoprotein Lipase Gene Polymorphisms and the Risk of Target Vessel Revascularization After Percutaneous Coronary Intervention J. Am. Coll. Cardiol., September 20, 2005; 46(6): 1093 - 1100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Chandiwal, V. Balasubramanian, Z. K. Baldwin, M. S. Conte, and L. B. Schwartz Gene Therapy for the Extension of Vein Graft Patency: A Review Vascular and Endovascular Surgery, January 1, 2005; 39(1): 1 - 14. [Abstract] [PDF]
|
|
|
|
 |
|
 L. Holterman, R. Vogels, R. van der Vlugt, M. Sieuwerts, J. Grimbergen, J. Kaspers, E. Geelen, E. van der Helm, A. Lemckert, G. Gillissen, et al. Novel Replication-Incompetent Vector Derived from Adenovirus Type 11 (Ad11) for Vaccination and Gene Therapy: Low Seroprevalence and Non-Cross-Reactivity with Ad5 J. Virol., December 1, 2004; 78(23): 13207 - 13215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Plaisier, K. Kapiteijn, P. Koolwijk, C. Fijten, R. Hanemaaijer, J. M. Grimbergen, A. Mulder-Stapel, P. H. A. Quax, F. M. Helmerhorst, and V. W. M. van Hinsbergh Involvement of Membrane-Type Matrix Metalloproteinases (MT-MMPs) in Capillary Tube Formation by Human Endometrial Microvascular Endothelial Cells: Role of MT3-MMP J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5828 - 5836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. van Weel, M. M.L. Deckers, J. M. Grimbergen, K. J.M. van Leuven, J. H.P. Lardenoye, R. O. Schlingemann, G. P. van Nieuw Amerongen, J. H. van Bockel, V. W.M. van Hinsbergh, and P. H.A. Quax Vascular Endothelial Growth Factor Overexpression in Ischemic Skeletal Muscle Enhances Myoglobin Expression In Vivo Circ. Res., July 9, 2004; 95(1): 58 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Collen, R. Hanemaaijer, F. Lupu, P. H. A. Quax, N. van Lent, J. Grimbergen, E. Peters, P. Koolwijk, and V. W. M. van Hinsbergh Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix Blood, March 1, 2003; 101(5): 1810 - 1817. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.L.M. Lamfers, J.M. Grimbergen, M.C. Aalders, M.J. Havenga, M.R. de Vries, L.G.M. Huisman, V.W.M. van Hinsbergh, and P.H.A. Quax 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 Circ. Res., November 15, 2002; 91(10): 945 - 952. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Shuhaiber, A. N. Evans, M. G. Massad, and A. S. Geha Mechanisms and future directions for prevention of vein graft failure in coronary bypass surgery Eur. J. Cardiothorac. Surg., September 1, 2002; 22(3): 387 - 396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.H.P. Lardenoye, M.R. de Vries, J.M. Grimbergen, L.M. Havekes, M.W.M. Knaapen, M.M. Kockx, V.W.M. van Hinsbergh, J.H. van Bockel, and P.H.A. Quax Inhibition of Accelerated Atherosclerosis in Vein Grafts by Placement of External Stent in ApoE*3-Leiden Transgenic Mice Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): 1433 - 1438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Engelse, J. H.P. Lardenoye, J. M. Neele, J. M. Grimbergen, M. R. de Vries, M. L.M. Lamfers, H. Pannekoek, P. H.A. Quax, and C. J.M. de Vries Adenoviral Activin A Expression Prevents Intimal Hyperplasia in Human and Murine Blood Vessels by Maintaining the Contractile Smooth Muscle Cell Phenotype Circ. Res., May 31, 2002; 90(10): 1128 - 1134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. E. Havenga, A. A. C. Lemckert, J. M. Grimbergen, R. Vogels, L. G. M. Huisman, D. Valerio, A. Bout, and P. H. A. Quax Improved Adenovirus Vectors for Infection of Cardiovascular Tissues J. Virol., April 1, 2001; 75(7): 3335 - 3342. [Abstract] [Full Text]
|
|