Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine
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 S...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/99184 https://orcid.org/0000-0002-7832-7156 |
| _version_ | 1826201308805201920 |
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| author | Baker, Aaron B. Chatzizisis, Yiannis S. Beigel, Roy Jonas, Michael Stone, Benjamin V. Coskun, Ahmet U. Maynard, Charles Rogers, Campbell Koskinas, Konstantinos C. Feldman, Charles L. Stone, Peter H. Edelman, Elazer R. |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Baker, Aaron B. Chatzizisis, Yiannis S. Beigel, Roy Jonas, Michael Stone, Benjamin V. Coskun, Ahmet U. Maynard, Charles Rogers, Campbell Koskinas, Konstantinos C. Feldman, Charles L. Stone, Peter H. Edelman, Elazer R. |
| author_sort | Baker, Aaron B. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:49:33Z |
| format | Article |
| id | mit-1721.1/99184 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:49:33Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/991842022-09-27T22:09:23Z Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine Baker, Aaron B. Chatzizisis, Yiannis S. Beigel, Roy Jonas, Michael Stone, Benjamin V. Coskun, Ahmet U. Maynard, Charles Rogers, Campbell Koskinas, Konstantinos C. Feldman, Charles L. Stone, Peter H. Edelman, Elazer R. Harvard University--MIT Division of Health Sciences and Technology Beigel, Roy Jonas, Michael Stone, Benjamin V. Edelman, Elazer R. 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. Novartis (Firm) Boston Scientific Corporation National Institutes of Health (U.S.) (Grant R01 GM49039) 2015-10-07T15:49:33Z 2015-10-07T15:49:33Z 2010-09 2010-08 Article http://purl.org/eprint/type/JournalArticle 00219150 http://hdl.handle.net/1721.1/99184 Baker, Aaron B., Yiannis S. Chatzizisis, Roy Beigel, Michael Jonas, Benjamin V. Stone, Ahmet U. Coskun, Charles Maynard, et al. “Regulation of Heparanase Expression in Coronary Artery Disease in Diabetic, Hyperlipidemic Swine.” Atherosclerosis 213, no. 2 (December 2010): 436–442. https://orcid.org/0000-0002-7832-7156 en_US http://dx.doi.org/10.1016/j.atherosclerosis.2010.09.003 Atherosclerosis Creative Commons Attribution-Noncommercial-NoDerivatives http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Baker, Aaron B. Chatzizisis, Yiannis S. Beigel, Roy Jonas, Michael Stone, Benjamin V. Coskun, Ahmet U. Maynard, Charles Rogers, Campbell Koskinas, Konstantinos C. Feldman, Charles L. Stone, Peter H. Edelman, Elazer R. Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine |
| title | Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine |
| title_full | Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine |
| title_fullStr | Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine |
| title_full_unstemmed | Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine |
| title_short | Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine |
| title_sort | regulation of heparanase expression in coronary artery disease in diabetic hyperlipidemic swine |
| url | http://hdl.handle.net/1721.1/99184 https://orcid.org/0000-0002-7832-7156 |
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