Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine

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

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)436-442
Number of pages7
JournalAtherosclerosis
Volume213
Issue number2
DOIs
StatePublished - Dec 1 2010

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Coronary Artery Disease
Swine
Staining and Labeling
Atherosclerotic Plaques
Atherosclerosis
Gelatinases
Heparan Sulfate Proteoglycans
Enzyme Assays
High Fat Diet
Metalloproteases
Hydrodynamics
Streptozocin
heparanase
Coronary Angiography
Matrix Metalloproteinases
Angiotensin II
Extracellular Matrix
Real-Time Polymerase Chain Reaction
Coronary Vessels
Macrophages

Keywords

  • Atherosclerosis
  • Endothelial shear stress
  • Heparanase
  • Thin cap fibroatheromas

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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.

In: Atherosclerosis, Vol. 213, No. 2, 01.12.2010, p. 436-442.

Research output: Contribution to journalArticle

Baker, AB, Chatzizisis, YS, Beigel, R, Jonas, M, Stone, BV, Coskun, AU, Maynard, C, Rogers, C, Koskinas, KC, Feldman, CL, Stone, PH & Edelman, ER 2010, 'Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine', Atherosclerosis, vol. 213, no. 2, pp. 436-442. https://doi.org/10.1016/j.atherosclerosis.2010.09.003
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. In: Atherosclerosis. 2010 ; Vol. 213, No. 2. pp. 436-442.
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