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 endogenous metalloproteinases (MMPs) within the aorta, particularly MMP-2 and MMP-9. This provides a potential therapeutic target for pharmacological agents aimed at reducing the growth rate of small aneurysms. In this study, the ability of marimastat (an MMP inhibitor) to reduce matrix degradation was assessed in a previously described model of aneurysm disease.


METHODS
Porcine aortic segments (n = 12) were preincubated in exogenous pancreatic 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 cultured both without marimastat and without elastase. At the termination of culture, 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 van Gieson's stain.


RESULTS
Stereological analysis demonstrated preservation of elastin in aorta 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 significant reduction in active MMP-2 activity in the samples treated with marimastat 10(-5) mol/l (P < 0.01).


CONCLUSIONS
Marimastat significantly inhibited elastin degradation and active MMP-2 production within aortic organ cultures.
Treharne
G D
GD
Department of Vascular Surgery, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK.
Boyle
J R
JR
Goodall
S
S
Loftus
I M
IM
Bell
P R
PR
Thompson
M M
MM
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology*; D002478:Cells, Cultured; D004549:Elastin / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology; D018093:Gelatinases / Q000187:drug effects* / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000187:drug effects* / Q000378:metabolism; D013552:Swine
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D004549:Elastin; C100342:marimastat; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2