Inhibition of smooth muscle cell migration and neointima formation in vein grafts by overexpression of matrix metalloproteinase-3.
OBJECTIVE
Saphenous 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.


METHODS
Human 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.


RESULTS
Migration 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.


CONCLUSIONS
MMP-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.
Kallenbach
Klaus
K
Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany. klaus.kallenbach@med.uni-heidelberg.de
Salcher
Rolf
R
Heim
Albert
A
Karck
Matthias
M
Mignatti
Paolo
P
Haverich
Axel
A
D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D002339:Carotid Arteries / Q000601:surgery; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D005260:Female; D006083:Graft Occlusion, Vascular / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007601:Jugular Veins / Q000201:enzymology* / Q000473:pathology / Q000637:transplantation; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D011817:Rabbits; D014161:Transduction, Genetic; D014182:Transplantation, Autologous; D017539:Tunica Intima / Q000201:enzymology* / Q000473:pathology
C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3