• Klaus Kallenbach, Rolf Salcher, Albert Heim, Matthias Karck, Paolo Mignatti, and Axel Haverich.
• Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany. klaus.kallenbach@med.uni-heidelberg.de
• J. Vasc. Surg. 2009 Mar 1; 49 (3): 750-8.

ObjectiveSaphenous vein grafts suffer from neointima formation following bypass surgery. Matrix metalloproteinases (MMPs) play important roles in this process. We examined MMP-3 for its therapeutic potential to prevent smooth muscle cell migration and neointima formation in venous bypass grafts using adenovirus-mediated gene transfer.MethodsHuman aortic smooth muscle cells (HASMC) were transduced with adenoviral vectors encoding ss-galactosidase (Ad.ssgal) [corrected] or human MMP-3 (Ad.hMMP-(3)), [corrected] and characterized for migration in the amniotic membrane stroma as an in vitro model of the vascular wall. Cholesterol-fed New Zealand white rabbits underwent jugular vein bypass grafting into carotid arteries. Before insertion, grafts were incubated ex vivo with either Ad.ssgal [corrected] or hMMP-3. Transgene expression was characterized by immunohistochemistry and in situ zymography. Grafts (n = 6) were explanted after 28 days and intimal hyperplasia was quantified.ResultsMigration of HASMC was significantly reduced when transduced with Ad.hMMP-(3) [corrected] compared to controls (P < .001). Immunocytochemistry of Ad.hMMP-(3) [corrected] transduced venous grafts localized this protein to the intima. In situ-zymography showed increased MMP activity in the intima of Ad.hMMP-(3) [corrected] transfected grafts. Stenosis degree (P = .001), intima/media-ratio (P = .023) and lesion thickness (P = .003) were significantly reduced in grafts transduced with Ad.MMP-3 in comparison to controls. There was no difference inside control groups.ConclusionMMP-3 overexpression inhibits formation of intimal hyperplasia in arterialized vein grafts. Adenovirus mediated gene transfer of MMP-3 may be of clinical use to prevent vein graft stenosis following bypass surgery.

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