Marimastat inhibits elastin degradation and matrix metalloproteinase 2 activity in a model of aneurysm disease

Background: Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, with a reduction in the elastin concentration of the arterial media. These changes have been linked to increased levels of e ndogenous metalloproteinases (MMPs) within the aorta, particularly MMP-2 an d MMP-9. This provides a potential therapeutic target for pharmacological a gents aimed at reducing the growth rate of small aneurysms. In this study, the ability of marimastat (an MMP inhibitor) to reduce matrix degradation w as assessed in a previously described model of aneurysm disease. Methods: Porcine aortic segments (n =12) were preincubated in exogenous pan creatic elastase for 24 h before culture in standard conditions for 13 days with marimastat 10(-5), 10(-6) and 10(-7) mol/l. Control segments were cul tured both without marimastat and without elastase. At the termination of c ulture, MMPs were extracted from the tissue and quantified by substrate gel enzymography. The volume fractions of elastin and collagen were determined by stereological analysis of sections stained with Miller's elastin and va n Gieson's stain. Results: Stereological analysis demonstrated preservation of elastin in aor ta treated with marimastat at 10(-6) and 10(-5) mol/l; this was significant at the latter concentration (P = 0.007). This was accompanied by a signifi cant reduction in active MMP-2 activity in the samples treated with marimas tat 10(-5) mol/l (P < 0.01). Conclusion: Marimastat significantly inhibited elastin degradation and acti ve MMP-2 production within aortic organ cultures.