| Differential Roles of Endothelin-1 in Angiotensin II-Induced Atherosclerosis and Aortic Aneurysms in Apolipoprotein E-Null Mice. | |
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MedLine Citation:
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PMID: 21718678 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Because both endothelin-1 (ET-1) and angiotensin II (AngII) are independent mediators of arterial remodeling, we sought to determine the role of ET receptor inhibition in AngII-accelerated atherosclerosis and aortic aneurysm formation. We administered saline or AngII and/or bosentan, an endothelin receptor antagonist (ERA) for 7, 14, or 28 days to 6-week- and 6-month-old apolipoprotein E-knockout mice. AngII treatment increased aortic atherosclerosis, which was reduced by ERA. ET-1 immunostaining was localized to macrophage-rich regions in aneurysmal vessels. ERA did not prevent AngII-induced aneurysm formation but instead may have increased aneurysm incidence. In AngII-treated animals with aneurysms, ERA had a profound effect on the non-aneurysmal thoracic aorta via increasing wall thickness, collagen/elastin ratio, wall stiffness, and viscous responses. These observations were confirmed in acute in vitro collagen sheet production models in which ERA inhibited AngII's dose-dependent effect on collagen type 1 α 1 (COL1A1) gene transcription. However, chronic treatment reduced matrix metalloproteinase 2 mRNA expression but enhanced COL3A1, tissue inhibitor of metalloproteinase 1 (TIMP1), and TIMP2 mRNA expressions. These data confirm a role for the ET system in AngII-accelerated atherosclerosis but suggest that ERA therapy is not protective against the formation of AngII-induced aneurysms and can paradoxically stimulate a chronic arterial matrix remodeling response. |
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Authors:
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Renée S Suen; Sarah N Rampersad; Duncan J Stewart; David W Courtman |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-6-27 |
Journal Detail:
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Title: The American journal of pathology Volume: - ISSN: 1525-2191 ISO Abbreviation: - Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-7-1 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Terrence Donnelly Research Laboratories, Division of Cardiology, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Ontario, Canada. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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