| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2000;101:296.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Inhibition of Late Vein Graft Neointima Formation in Human and Porcine Models by Adenovirus-Mediated Overexpression of Tissue Inhibitor of Metalloproteinase-3
From the Bristol Heart Institute, University of Bristol, Bristol, UK. Dr Baker’s current address is Dept of Medicine and Therapeutics, University of Glasgow, Western Infirmary, Glasgow G116NT, UK.
Correspondence to Sarah J. George, PhD, Bristol Heart Institute, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK. E-mail s.j.george{at}bris.ac.uk
Background—Autologous saphenous vein coronary artery bypass graft surgery is complicated by late graft failure due to neointima formation and subsequent atherosclerosis. Growth factors and metalloproteinases (MMPs) act in concert to promote neointima formation. Tissue inhibitor of metalloproteinase-3 (TIMP-3), an extracellular matrix–associated MMP inhibitor, uniquely promotes apoptosis of isolated vascular smooth muscle cells. Here, we overexpressed TIMP-3 at the luminal surface of human saphenous veins before organ culture and in pig saphenous veins before interposition grafting into carotid arteries in vivo to assess neointima formation.
Methods and Results—In both models, high TIMP-3 immunoreactivity occurred in the luminal and upper medial extracellular matrix after adenovirus delivery. MMP activity measured by in situ zymography was reduced throughout the veins, confirming a bystander effect. By use of 3 independent techniques, apoptosis levels in the neointima and medial layer were significantly elevated by TIMP-3 overexpression. Neointima formation was reduced by 84% in 14-day human organ cultures and by 58% in 28-day pig vein grafts (both P<0.05). In contrast, TIMP-2 overexpression had no effect on neointima formation in vivo.
Conclusions—Our results highlight the potential therapeutic benefit for TIMP-3 overexpression to reduce neointima formation associated with late vein graft failure.
Key Words: metalloproteinases • genes • viruses • grafting • neointima
This article has been cited by other articles:
 |
|
 |
|
  T. Schachner, G. Laufer, and J. Bonatti In vivo (animal) models of vein graft disease. Eur. J. Cardiothorac. Surg., September 1, 2006; 30(3): 451 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Sharony, G. Pintucci, P. C. Saunders, E. A. Grossi, F. G. Baumann, A. C. Galloway, and P. Mignatti Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2 Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1651 - H1659. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Newby Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates Cardiovasc Res, February 15, 2006; 69(3): 614 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W.M. Fedak, P. E. Szmitko, R. D. Weisel, S. M. Altamentova, N. Nili, N. Ohno, S. Verma, S. Fazel, B. H. Strauss, and R.-K. Li Cell transplantation preserves matrix homeostasis: A novel paracrine mechanism J. Thorac. Cardiovasc. Surg., November 1, 2005; 130(5): 1430 - 1439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamaoka, Y. Yonemitsu, K. Komori, H. Baba, T. Matsumoto, T. Onohara, and Y. Maehara Ex vivo electroporation as a potent new strategy for nonviral gene transfer into autologous vein grafts Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1865 - H1872. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. W. Johnson, Y. X. Wu, C. Herdeg, A. Baumbach, A. C. Newby, K. R. Karsch, and M. Oberhoff Stent-Based Delivery of Tissue Inhibitor of Metalloproteinase-3 Adenovirus Inhibits Neointimal Formation in Porcine Coronary Arteries Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 754 - 759. [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]
|
|
|
|
 |
|
 A. C. Newby Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture Physiol Rev, January 1, 2005; 85(1): 1 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Anstadt, D. L. Franga, V. Portik-Dobos, A. Pennathur, M. Bannan, K. Mawulawde, and A. Ergul Native Matrix Metalloproteinase Characteristics May Influence Early Stenosis of Venous Versus Arterial Coronary Artery Bypass Grafting Conduits Chest, May 1, 2004; 125(5): 1853 - 1858. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. F. Akowuah, P. J. Sheridan, G. J. Cooper, and C. Newman Preventing saphenous vein graft failure: does gene therapy have a role? Ann. Thorac. Surg., September 1, 2003; 76(3): 959 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M Aguilera, S. J George, J. L Johnson, and A. C Newby Relationship between type IV collagen degradation, metalloproteinase activity and smooth muscle cell migration and proliferation in cultured human saphenous vein Cardiovasc Res, June 1, 2003; 58(3): 679 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Forrester Prevention of Plaque Rupture: A New Paradigm of Therapy Ann Intern Med, November 19, 2002; 137(10): 823 - 833. [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]
|
|
|
|
 |
|
 W. W. Spurbeck, C. Y. C. Ng, T. S. Strom, E. F. Vanin, and A. M. Davidoff Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model Blood, October 16, 2002; 100(9): 3361 - 3368. [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]
|
|
|
|
 |
|
 J. H. Qi, Q. Ebrahem, K. Yeow, D. R. Edwards, P. L. Fox, and B. Anand-Apte Expression of Sorsby's Fundus Dystrophy Mutations in Human Retinal Pigment Epithelial Cells Reduces Matrix Metalloproteinase Inhibition and May Promote Angiogenesis J. Biol. Chem., April 12, 2002; 277(16): 13394 - 13400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bond, G. Murphy, M. R. Bennett, A. C. Newby, and A. H. Baker Tissue Inhibitor of Metalloproteinase-3 Induces a Fas-associated Death Domain-dependent Type II Apoptotic Pathway J. Biol. Chem., April 12, 2002; 277(16): 13787 - 13795. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Baker, D. R. Edwards, and G. Murphy Metalloproteinase inhibitors: biological actions and therapeutic opportunities J. Cell Sci., January 10, 2002; 115(19): 3719 - 3727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hu, A. H. Baker, Y. Zou, A. C. Newby, and Q. Xu Local Gene Transfer of Tissue Inhibitor of Metalloproteinase-2 Influences Vein Graft Remodeling in a Mouse Model Arterioscler. Thromb. Vasc. Biol., August 1, 2001; 21(8): 1275 - 1280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Johnson, G. J. J. M. van Eys, G. D. Angelini, and S. J. George Injury Induces Dedifferentiation of Smooth Muscle Cells and Increased Matrix-Degrading Metalloproteinase Activity in Human Saphenous Vein Arterioscler. Thromb. Vasc. Biol., July 1, 2001; 21(7): 1146 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Nicklin, P. N. Reynolds, M. J. Brosnan, S. J. White, D. T. Curiel, A. F. Dominiczak, and A. H. Baker Analysis of Cell-Specific Promoters for Viral Gene Therapy Targeted at the Vascular Endothelium Hypertension, July 1, 2001; 38(1): 65 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ju, R. Gros, X. You, S. Tsang, M. Husain, and M. Rabinovitch Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice PNAS, June 19, 2001; 98(13): 7469 - 7474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. J. Dzau, M. J. Mann, A. Ehsan, and D. P. Griese Gene therapy and genomic strategies for cardiovascular surgery: The emerging field of surgiomics J. Thorac. Cardiovasc. Surg., February 1, 2001; 121(2): 0206 - 216. [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. LaMuraglia, J. Schiereck, J. Heckenkamp, G. Nigri, P. Waterman, D. Leszczynski, and S. Kossodo Photodynamic Therapy Induces Apoptosis in Intimal Hyperplastic Arteries Am. J. Pathol., September 1, 2000; 157(3): 867 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Loscalzo Vascular Matrix and Vein Graft Failure : Is the Message in the Medium? Circulation, January 25, 2000; 101(3): 221 - 223. [Full Text] [PDF]
|
|
|
|
|
|
M. Bond, G. Murphy, M. R Bennett, A. Amour, V. Knauper, A. C. Newby, and A. H. Baker Localization of the Death Domain of Tissue Inhibitor of Metalloproteinase-3 to the N Terminus. METALLOPROTEINASE INHIBITION IS ASSOCIATED WITH PROAPOPTOTIC ACTIVITY J. Biol. Chem., December 22, 2000; 275(52): 41358 - 41363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Qian, K. Channon, V. Neplioueva, Q. Wang, M. Finer, L. Tsui, S. E. George, and J. McArthur Improved Adenoviral Vector for Vascular Gene Therapy : Beneficial Effects on Vascular Function and Inflammation Circ. Res., May 11, 2001; 88(9): 911 - 917. [Abstract] [Full Text] [PDF]
|
|