Marimastat inhibits neointimal thickening in a model of human arterial intimal hyperplasia.
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).


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.
Peterson
M
M
Department of Surgery, Robert Kilpatrick Clinical Sciences Building, Leicester, LE2 7LX, U.K.
Porter
K E
KE
Loftus
I M
IM
Thompson
M M
MM
London
N J
NJ
D002478:Cells, Cultured; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000601:surgery; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006083:Graft Occlusion, Vascular / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D006965:Hyperplasia / Q000517:prevention & control; D008323:Mammary Arteries / Q000187:drug effects / Q000201:enzymology / Q000473:pathology* / Q000637:transplantation; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017539:Tunica Intima / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C100342:marimastat; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9