GENE-TRANSFER OF TISSUE INHIBITOR OF METALLOPROTEINASE-2 INHIBITS METALLOPROTEINASE ACTIVITY AND NEOINTIMA FORMATION IN HUMAN SAPHENOUS VEINS

Metalloproteinases (MMPs) are implicated in neointima formation and he nce Vein graft failure. Gene transfer to elevate local levels of tissu e inhibitor of metalloproteinases (TIMPs) is therefore a potential tre atment In this study, we have used lumenal application of a replicatio n-defective recombinant adenovirus to overexpress TIMP-2 and observe t he effects on neointimal thickening in a well characterised human saph enous vein organ culture model. Increased TIMP-2 expression was locali sed to lumenal surface cells hut nevertheless increased total function al TIMP-2 secretion after 14 days culture from 4.0 +/- 20 to 21.8 +/- 29 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 o verexpression had no effect on smooth muscle cell proliferation, secre tion of pro-MMP-2 or -9 and did not inhibit the processing of pro-MMP- 2 to ifs active form. Our data indicate that TIMP-2 overexpression red uces neointimal thickening, primarily by inhibiting MMP activity and h ence smooth muscle cell migration.