Adenovirus-Mediated Gene Transfer of the Human TIMP-1 Gene Inhibits Smooth Muscle Cell Migration and Neointimal Formation in Human Saphenous Vein

Publisher Website
Google Scholar
Abstract
Neointimal formation involving smooth muscle cell (SMC) migration and proliferation is a common feature of atherosclerosis, restenosis after angioplasty, and vein graft intimal thickening. Extracellular matrix remodeling 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 formation in human saphenous vein to investigate the effect of adenovirus-mediated gene transfer of tissue inhibitor of metalloproteinase 1 (TIMP-1) and the bacterial LacZ gene (RAd35) as a control. Incubating veins with 100 μl of RAd35 (1.2 × 1010 pfu/ml) led to expression of LacZ in 39 ± 7% of surface cells but had no effect on SMC proliferation, migration, or neointimal formation. Similar infection with RAdTIMP-1 increased explanation of TIMP-1 in surface cells and significantly inhibited neointimal formation and SMC migration after 14 days by 54% and 78%, respectively (n = 6, p < 0.05 Student's paired t test). No effect on SMC proliferation or deleterious effect on cell viability was observed. A specific MMP inhibitory effect was detected using in situ zymography. These data confirm the importance of MMPs in neointimal formation and highlight the potential for application of TIMP gene therapy. We tested the concept that adenovirus-mediated gene transfer of a tissue inhibitor of matrix-degrading metalloproteinases (TIMP-1) would inhibit neointimal formation in human saphenous vein segments in organ culture. We achieved efficient infection and expression in lumenal cells of the human TIMP-1 gene and bacterial LacZ gene as a control. TIMP-1 expression significantly reduced SMC migration and neointimal formation but not SMC proliferation or cell viability. This study demonstrates the importance of MMP activity in neointimal formation and supports the potential application of TIMP-1 in gene therapy.

This publication has 34 references indexed in Scilit: