Document Detail

Production and inhibition of the gelatinolytic matrix metalloproteinases in a human model of vein graft stenosis.
MedLine Citation:
PMID:  10329524     Owner:  NLM     Status:  MEDLINE    
OBJECTIVES: human vein graft stenoses are caused by intimal hyperplasia, a process which is characterised by extensive degradation and accumulation of extracellular matrix. This study investigated the role of the matrix metalloproteinases (MMPs) - the principal physiological mediators of extracellular matrix degradation - in the development of intimal hyperplasia in cultured human long saphenous vein. DESIGN: experimental study. MATERIALS AND METHODS: paired venous segments with the endothelium intact or denuded were cultured in standard conditions for 14 days. At the termination of culture, MMPs were extracted from one half of the tissue, whilst the remainder of the vein was prepared for histological examination. RESULTS: stereologic analysis revealed that the endothelium intact veins developed a significantly thicker neointima when compared to the denuded venous segments (20 micron v. 0 micron, p=0.006). Quantification of MMPs by substrate gel enzymography demonstrated that the development of a neointima was associated with increased production of the gelatinolytic MMP-9 (p=0. 03) in intact veins. Immunocytochemistry showed that the MMP-9 localised to the internal elastic lumina, which suggested a role in facilitating smooth-muscle-cell migration into the intima. The role of MMPs-2 and -9 in intimal hyperplasia was further investigated by culturing intact venous segments with a therapeutic concentration of doxycycline--a potent MMP inhibitor. These experiments demonstrated that a therapeutic dose of doxycycline significantly reduced neointimal thickness (control 21 micron, doxycycline 10 mg/l-5.5 micron), in conjunction with a significant reduction in the production of MMP-9. CONCLUSIONS: these data suggest that elevated levels of MMPs may play a significant role in the development of human intimal hyperplasia and that inhibition of these enzymes may offer a potential therapeutic strategy for the prevention of hyperplastic lesions.
K E Porter; M M Thompson; I M Loftus; E McDermott; L Jones; M Crowther; P R Bell; N J London
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery     Volume:  17     ISSN:  1078-5884     ISO Abbreviation:  Eur J Vasc Endovasc Surg     Publication Date:  1999 May 
Date Detail:
Created Date:  1999-07-23     Completed Date:  1999-07-23     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9512728     Medline TA:  Eur J Vasc Endovasc Surg     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  404-12     Citation Subset:  IM    
Copyright Information:
Copyright 1999 W.B. Saunders Company Ltd.
Department of Surgery, University of Leicester, U.K.
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MeSH Terms
Anti-Bacterial Agents / pharmacology
Blotting, Western / methods
Collagenases / analysis,  antagonists & inhibitors*,  biosynthesis*
Doxycycline / pharmacology
Endothelium, Vascular / drug effects,  enzymology
Gelatin / pharmacokinetics*
Gelatinases / analysis,  antagonists & inhibitors*,  biosynthesis*
Graft Occlusion, Vascular / enzymology*
Hyperplasia / enzymology
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Metalloendopeptidases / analysis,  antagonists & inhibitors*,  biosynthesis*
Organ Culture Techniques / methods
Saphenous Vein / drug effects,  enzymology*,  pathology
Statistics, Nonparametric
Tunica Intima / drug effects,  enzymology*,  pathology
Reg. No./Substance:
0/Anti-Bacterial Agents; 564-25-0/Doxycycline; 9000-70-8/Gelatin; EC 3.4.24.-/Collagenases; EC 3.4.24.-/Gelatinases; EC 3.4.24.-/Metalloendopeptidases; EC Metalloproteinase 2; EC Metalloproteinase 9

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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