MODULATION OF MATRIX METALLOPROTEINASE ACTIVITY IN HUMAN SAPHENOUS-VEIN GRAFTS USING ADENOVIRUS-MEDIATED GENE-TRANSFER

Background. Neointima formation after human saphenous vein grafting (h SVG) involves several matrix metalloproteinases (MMPs) and their tissu e inhibitors (TIMPs). This study assessed the feasibility of modulatin g MMP activity in hSVGs by adrenovirus-mediated gene transfer. Methods . First, 1 x 10(9) plaque-forming units (pfu) of replication-deficient recombinant adenoviruses encoding either beta-galactosidase (Ad beta gal), MMP-3 (AdMMP-3), or (TIMP-1) were added into the lumen of hSVGs for 1 hour. After incubation at 37 degrees C for 24 hours, specimens w ere analyzed by immunohistochemistry, in situ zymography, and X-gal st aining. Results, By X-gal staining Ad beta gal-infected hSVGs stained positively in the intima and occasionally in the media. Immunohistoche mistry of AdMMP-3- and AdTIMP-1-infected hSVGs localized these protein s to the intima. In situ zymography showed increased MMP activity in t he intima of AdMMP-3-infected hSVGs relative to AdTIMP-1- or Ad beta g al-infected vessels. Conclusions. MMP-3 and TIMP activity can be regul ated in hSVGs by replication-deficient recombinant adenoviruses. We ha ve previously demonstrated that MMP-3 or TIMP-1 transduction, or both, inhibit SMC migration in an in vitro reconstituted vessel wall. Modul ation of MMP activity may thus afford high patency rates in geneticall y engineered hSVGs. However, adenovirus-mediated gene delivery is limi ted to the vessel's intima; strategies to infect medial smooth muscle cells need to be developed.