Document Detail


Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine.
MedLine Citation:
PMID:  20950809     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Enzymatic degradation of the extracellular matrix is known to be powerful regulator of atherosclerosis. However, little is known about the enzymatic regulation of heparan sulfate proteoglycans (HSPGs) during the formation and progression of atherosclerotic plaques.
METHODS AND RESULTS: Swine were rendered diabetic through streptozotocin injection and hyperlipidemic through a high fat diet. Arterial remodeling and local endothelial shear stress (ESS) were assessed using intravascular ultrasound, coronary angiography and computational fluid dynamics at weeks 23 and 30. Coronary arteries were harvested and 142 arterial subsegments were analyzed using histomorphologic staining, immunostaining and real time PCR. Heparanase staining and activity was increased in arterial segments with low ESS, in lesions with thin cap fibroatheroma (TCFA) morphology and in lesions with severely degraded internal elastic laminae. In addition, heparanase staining co-localized with staining for CD45 and MMP-2 within atherosclerotic plaques. Dual staining with gelatinase zymography and heparanase immunohistochemical staining demonstrated co-localization of matrix metalloprotease activity with heparanase staining. A heparanase enzymatic activity assay demonstrated increased activity in TCFA lesions, subsegments with low ESS and in macrophages treated with oxidized LDL or angiotensin II.
CONCLUSIONS: Taken together, our results support a critical role for heparanase in the development of vulnerable plaques and suggest a novel therapeutic target for the treatment of atherosclerosis.
Authors:
Aaron B Baker; Yiannis S Chatzizisis; Roy Beigel; Michael Jonas; Benjamin V Stone; Ahmet U Coskun; Charles Maynard; Campbell Rogers; Konstantinos C Koskinas; Charles L Feldman; Peter H Stone; Elazer R Edelman
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Publication Detail:
Type:  Journal Article     Date:  2010-09-18
Journal Detail:
Title:  Atherosclerosis     Volume:  213     ISSN:  1879-1484     ISO Abbreviation:  Atherosclerosis     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-06     Completed Date:  2011-03-18     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  0242543     Medline TA:  Atherosclerosis     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  436-42     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD45 / metabolism
Coronary Artery Disease / metabolism*,  pathology
Diabetes Mellitus, Experimental / enzymology*
Dietary Fats / administration & dosage
Gene Expression Regulation, Enzymologic
Glucuronidase / biosynthesis*
Heparan Sulfate Proteoglycans / metabolism
Hyperlipidemias / enzymology*
Male
Matrix Metalloproteinase 2 / metabolism
Plaque, Atherosclerotic / enzymology
Swine
Grant Support
ID/Acronym/Agency:
R01 GM049039/GM/NIGMS NIH HHS; R01 GM049039-15/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Dietary Fats; 0/Heparan Sulfate Proteoglycans; EC 3.1.3.48/Antigens, CD45; EC 3.2.1.-/heparanase; EC 3.2.1.31/Glucuronidase; EC 3.4.24.24/Matrix Metalloproteinase 2
Comments/Corrections

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


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