Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3

Background-Autologous saphenous vein coronary artery bypass graft surgery i s complicated by late graft failure due to neointima formation and subseque nt atherosclerosis. Growth factors and metalloproteinases (MMPs) act in con cert to promote neointima formation. Tissue inhibitor of metalloproteinase- 3 (TIMP-3), an extracellular matrix-associated MMP inhibitor, uniquely prom otes apoptosis of isolated vascular smooth muscle cells. Here, we overexpre ssed TIMP-3 at the luminal surface of human saphenous veins before organ cu lture and in pig saphenous veins before interposition grafting into carotid arteries in vivo to assess neointima formation. Method and Results-In both models, high TIMP-3 immunoreactivity occurred in the luminal and upper medial extracellular matrix after adenovirus deliver y. MMP activity measured by in situ zymography was reduced throughout the v eins, confirming a bystander effect. By use of 3 independent techniques, ap optosis levels in the neointima and medial layer were significantly elevate d by TIMP-3 overexpression, Neointima formation was reduced by 84% in 14-da y human organ cultures and by 58% in 28-day pig vein grafts (both P<0.05). In contrast, TIMP-2 overexpression had no effect on neointima formation in vivo. Conclusions-Our results highlight the potential therapeutic benefit for TIM P-3 overexpression to reduce neointima formation associated with late vein graft failure.