Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3

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),...

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Published in:Circulation (New York, N.Y.) N.Y.), 2000-01, Vol.101 (3), p.296-304
Main Authors: GEORGE, S. J, LLOYD, C. T, ANGELINI, G. D, NEWBY, A. C, BAKER, A. H
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Animals
Apoptosis
Biological and medical sciences
Genetic Therapy
Humans
Medical sciences
Postoperative Complications - prevention & control
Recombinant Proteins - analysis
Saphenous Vein - transplantation
Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases
Surgery of the heart
Swine
Tissue Inhibitor of Metalloproteinase-2 - physiology
Tissue Inhibitor of Metalloproteinase-3 - analysis
Tissue Inhibitor of Metalloproteinase-3 - genetics
Tissue Inhibitor of Metalloproteinase-3 - physiology
Tunica Intima - pathology
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Summary: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. 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
ISSN:0009-7322
1524-4539
DOI:10.1161/01.cir.101.3.296