Abstract
Metalloproteinases (MMPs) are implicated in neointima formation and hence vein graft failure. Gene transfer to elevate local levels of tissue inhibitor of metalloproteinases (TIMPs) is therefore a potential treatment. In this study, we have used lumenal application of a replication-defective recombinant adenovirus to overexpress TIMP-2 and observe the effects on neointimal thickening in a well characterised human saphenous vein organ culture model. Increased TIMP-2 expression was localised to lumenal surface cells but nevertheless increased total functional TIMP-2 secretion after 14 days culture from 4.0 ± 2.0 to 21.8 ± 2.9 ng/mg wet weight/day (P < 0.05, n = 3). in situ zymography revealed a marked inhibition of gelatinolytic activity by timp-2 gene transfer throughout the vein segments. neointima formation and neointimal cell numbers were reduced 79% and 71%, respectively (p < 0.05; n = 8). timp-2 overexpression had no effect on smooth muscle cell proliferation, secretion of pro-mmp-2 or -9 and did not inhibit the processing of pro-mmp-2 to its active form. our data indicate that timp-2 overexpression reduces neointimal thickening, primarily by inhibiting mmp activity and hence smooth muscle cell migration.
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George, S., Baker, A., Angelini, G. et al. Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins. Gene Ther 5, 1552–1560 (1998). https://doi.org/10.1038/sj.gt.3300764
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DOI: https://doi.org/10.1038/sj.gt.3300764
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