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Marimastat inhibits neointimal thickening in a model of human arterial intimal hyperplasia
M Peterson1, K E Porter, I M Loftus
1Department of Surgery, Robert Kilpatrick Clinical Sciences Building, Leicester, LE2 7LX, U.K.
Objective:
matrix metalloproteases (MMPs) produced by vascular smooth-muscle cells (VSMCs) degrade extracellular matrix and facilitate the migration of these cells. This is a fundamental process in arterial intimal hyperplasia. This study investigated whether Marimastat (a selective but non-specific MMP inhibitor) can prevent intimal hyperplasia in cultured human internal mammary artery (IMA).
Materials And Methods:
segments of IMA from 8 patients were prepared and cultured for 14 days in serum-supplemented medium (control) or in medium supplemented with Marimastat at 2 concentrations (treatment groups). The tissue was fixed, sectioned, stained and neointimal thicknesses measured by computer-aided image analysis. Further sections were cultured in the same manner and prepared for gel enzymography to quantify the production of MMPs.
Results:
neointimal thickness was significantly reduced by Marimastat in a dose-dependent manner when compared to controls (p =0.008 Wilcoxon). Gel enzymography demonstrated a reduction in levels of MMP2 and MMP9. This was most significant for the active forms of the enzymes ( p =0.03).
Conclusions:
our results suggest that there is a potential therapeutic role for specific inhibition of the gelatinases in the prevention of human arterial restenosis.
Insights
Marimastat significantly reduced arterial intimal hyperplasia in human internal mammary artery cultures. This MMP inhibitor decreased neointimal thickness and gelatinase levels, suggesting a therapeutic role in preventing restenosis.
Area of Science:
- Cardiovascular Biology
- Vascular Cell Biology
- Matrix Biology
Background:
- Vascular smooth muscle cell (VSMC) migration, driven by matrix metalloproteinases (MMPs), is crucial for arterial intimal hyperplasia.
- Understanding the role of MMPs in intimal hyperplasia is key to developing treatments for vascular diseases.
Purpose of the Study:
- To investigate the efficacy of Marimastat, a matrix metalloproteinase inhibitor, in preventing intimal hyperplasia in cultured human internal mammary artery (IMA).
Main Methods:
- Human IMA segments were cultured for 14 days with or without Marimastat at two concentrations.
- Neointimal thickness was quantified using computer-aided image analysis.
- Matrix metalloproteinase production was assessed using gel enzymography.
Main Results:
- Marimastat significantly reduced neointimal thickness in a dose-dependent manner compared to controls (p = 0.008).
- Gel enzymography revealed decreased levels of MMP2 and MMP9, particularly their active forms (p = 0.03).
Conclusions:
- Inhibition of matrix metalloproteinases, specifically gelatinases, shows potential for preventing human arterial restenosis.
- Marimastat demonstrates a therapeutic possibility in managing conditions characterized by intimal hyperplasia.
