[Adenovirus-mediated transfer of TIMP-4 gene inhibits neointimal formation after balloon injury].

OBJECTIVE: To investigate the effects of human tissue inhibitor of matelloproteinase-4 (TIMP-4) on vascular smooth muscle cells (VSMCs) migration and the neointimal formation after balloon injury in rats. METHODS: The cultured VSMCs were transfected with an adenoviral vector containing human TIMP-4 gene, AdTIMP-4. Effect of TIMP-4 on VSMC migration was investigated by monolayer cell scrape. AdTIMP-4, control adenoviral vector or PBS was transduced into the rat carotid artery from the adventitial after carotid artery injury. Cell number within the internal elastic lamina 4 days after gene transfer was counted and neointima/media area ratio 28 days after gene transfer was calculated. RESULTS: The migration distance of VSMCs infected with AdTIMP-4 was inhibited markedly. Morphometric analysis demonstrated a statistically significant reduction in the number of cells migrated into neointima compared with controls [(32.5 +/- 4.8) cells per section, (33.8 +/- 7.0) cells per section and (8.2 +/- 2.4) cells per section for uninfected, AdGFP-treated and AdTIMP-4-treated arteries, respectively]. There was a reduction of intima/media ratio of TIMP-4-treated group by 66.5% compared with control groups 28 days after gene transfer (P < 0.01). There was no statistical difference between the control adenoviral vector group and PBS group. CONCLUSION: Adenoviral mediated gene transfer of TIMP-4 inhibits migration of VSMC and significantly reduces neointimal hyperplasia in the rat carotid balloon injury model. The TIMP-4 gene transfer is a potential therapeutic approach to preventing neointimal formation after balloon injury.