Abstract 3718: Reduction of Neointima Formation in Autologous Vein Grafts in vivo by Overexpression of Matrix Metalloproteinase-3 (Stromeylsin-1)
Objective: Autologous human saphenous vein suffers from neointima formation in coronary artery bypass surgery. Paradoxically, Stromelysin-1 (MMP-3) may prevent development of vascular lesions in coronary arteries. We examined human matrix metalloproteinase-3 (hMMP-3) for its therapeutic potential against neointima formation in venous bypass grafts in vivo using adenovirus-mediated gene transfer.
Methods: Cholesterol fed New Zealand White Rabbits underwent autologous jugularis vein bypass grafting into carotid arteries. Before vein graft was inserted either Polaxamer 407, PBS, or adenoviral vectors encoding for β-galactosidase (Ad. βgal) or Stromelysin-1 (Ad.hMMP-3) were added into the lumen and incubated at 37°C for 45′ minutes ex vivo, respectively. Grafts were analyzed for transgene overexpression by immunohistochemistry, in situ-zymography and βgal-staining seven days after interposition. For morphological and morphometrical analysis grafts (n=6) were explanted after 28 days and stained with H&E and vanGieson. Stenosis degree, intima/media-ratio and lesion thickness were measured and statistically analyzed.
Results: Immunohistochemistry of Ad.hMMP-3 transfected grafts localized this protein to the intima. Gelatine in situ-zymography showed increased MMP activity in the intima of Ad.hMMP-3 transfected grafts. By βgal-staining, Ad. βgal transfected grafts stained positively in the intima. Morphological and morphometrical analysis of development of neointima formation demonstrated significant reduction of stenosis degree (p=0,001), intima/media-ratio (p=0,023) and lesion thickness (p=0,003) in grafts transfected with Ad.MMP-3 in comparison to other groups (controls). There was no difference inside the control groups.
Conclusions: We demonstrated for the first time the therapeutic potential of hMMP-3 for reduction of neointima formation of autologous vein grafting in vivo. Overexpression of hMMP-3 may prevent vein graft stenosis in coronary bypass surgery clinically.