Marimastat inhibits neointimal thickening in a model of human vein graft stenosis.
BACKGROUND
There is now accumulating evidence that matrix metalloproteinases (MMPs), the physiological mediators of matrix deposition and degradation, play an important role in the development of intimal hyperplasia following arterial bypass. This study investigated the effect of marimastat, an orally active specific MMP inhibitor, on neointima formation in cultured human saphenous vein.


METHODS
Segments of human saphenous vein obtained from ten patients undergoing arterial bypass surgery were cultured for 14 days in serum-supplemented RPMI medium (controls) or in control medium supplemented with marimastat at three different concentrations (treatment groups). Following culture, half of each segment was prepared for histological examination and MMPs were extracted from the other half for gelatin zymography.


RESULTS
Marimastat inhibited neointimal thickening in a concentration-dependent manner; inhibition was significant at 10(-5) and 10(-6) mol/l (P=0.006). This observation was paralleled by a significant reduction in the levels of MMP-2 and MMP-9 in the tissues.


CONCLUSIONS
Marimastat significantly reduced neointimal thickening in this laboratory model. MMP inhibitors may offer a potential therapeutic strategy in the prevention of intimal hyperplasia.
Department of Surgery, University of Leicester, Leicester Royal Infirmary, UK.
K E
KE
Porter
I M
IM
Loftus
M
M
Peterson
P R
PR
Bell
N J
NJ
London
M M
MM
Thompson
D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D012501:Saphenous Vein / Q000187:drug effects*; D017539:Tunica Intima / Q000187:drug effects*
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C100342:marimastat