ADENOVIRUS-MEDIATED GENE-TRANSFER OF THE HUMAN TIMP-1 GENE INHIBITS SMOOTH-MUSCLE CELL-MIGRATION AND NEOINTIMAL FORMATION IN HUMAN SAPHENOUS-VEIN

Neointimal formation involving smooth muscle cell (SMC)migration and p roliferation is a common feature of atherosclerosis, restenosis after angioplasty, and vein graft intimal thickening. Extracellular matrix r emodeling by metalloproteinase (MMP) enzymes is an essential component of neointimal formation and therefore MMPs are a potential target for localized gene therapy, To evaluate this concept using human tissue, we used the highly reproducible organ culture model of neointimal form ation in human saphenous vein to investigate the effect of adenovirus- mediated gene transfer of tissue inhibitor of metalloproteinase 1 (TIM P-1) and the bacterial LacZ gene (RAd35) as a control. Incubating vein s with 100 mu l of RAd35 (1.2 x 10(10) pfu/ml) led to expression of La cZ in 39 +/- 7% of surface cells but had no effect on SMC proliferatio n, migration, or neointimal formation. Similar infection with RAdTIMP- 1 increased explanation of TIMP-1 in surface cells and significantly i nhibited neointimal formation and SMC migration after 14 days by 54% a nd 78%, respectively (n = 6, p < 0.05 Student's paired t test). No eff ect on SMC proliferation or deleterious effect on cell viability was o bserved. A specific MMP inhibitory effect was detected using in situ z ymography, These data confirm the importance of MMPs in neointimal for mation and highlight the potential for application of TIMP gene therap y.