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Marimastat inhibits neointimal thickening in a model of human vein graft stenosis
K E Porter1, I M Loftus, M Peterson
1Department of Surgery, University of Leicester, Leicester Royal Infirmary, UK.
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.
Conclusion:
Marimastat significantly reduced neointimal thickening in this laboratory model. MMP inhibitors may offer a potential therapeutic strategy in the prevention of intimal hyperplasia.
Insights
Marimastat, a matrix metalloproteinase (MMP) inhibitor, significantly reduced neointimal thickening in human saphenous vein cultures. This suggests MMP inhibitors could be a therapeutic strategy for preventing intimal hyperplasia after arterial bypass.
Area of Science:
- Vascular Biology
- Pharmacology
Background:
- Matrix metalloproteinases (MMPs) mediate matrix remodeling and are implicated in intimal hyperplasia post-arterial bypass.
- Intimal hyperplasia is a significant complication following arterial bypass surgery.
Purpose of the Study:
- To investigate the effect of marimastat, a specific MMP inhibitor, on neointima formation in cultured human saphenous vein.
- To assess the impact of marimastat on MMP activity in arterial tissue.
Main Methods:
- Human saphenous vein segments were cultured for 14 days with varying concentrations of marimastat.
- Histological examination assessed neointimal thickening.
- Gelatin zymography quantified MMP-2 and MMP-9 levels.
Main Results:
- Marimastat demonstrated a concentration-dependent inhibition of neointimal thickening.
- Significant inhibition was observed at 10(-5) and 10(-6) mol/l.
- A parallel reduction in MMP-2 and MMP-9 levels was noted in marimastat-treated tissues.
Conclusions:
- Marimastat effectively reduced neointimal thickening in a human saphenous vein model.
- MMP inhibitors represent a potential therapeutic avenue for preventing intimal hyperplasia.