Document Detail


Differential roles of endothelin-1 in angiotensin II-induced atherosclerosis and aortic aneurysms in apolipoprotein E-null mice.
MedLine Citation:
PMID:  21718678     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 (TIMP-1), and TIMP-2 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.
Authors:
Renée S Suen; Sarah N Rampersad; Duncan J Stewart; David W Courtman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-06-29
Journal Detail:
Title:  The American journal of pathology     Volume:  179     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-22     Completed Date:  2011-12-09     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1549-59     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Affiliation:
Terrence Donnelly Research Laboratories, Division of Cardiology, St. Michael's Hospital, Toronto, Ontario, Canada.
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MeSH Terms
Descriptor/Qualifier:
Angiotensin II / adverse effects*
Animals
Antigens, CD29 / metabolism
Antihypertensive Agents / pharmacology
Aorta / physiology
Aortic Aneurysm / chemically induced*
Apolipoproteins E*
Atherosclerosis / chemically induced*
Biomechanics
Cardiovascular Agents / pharmacology
Cell Adhesion
Collagen / metabolism
Down-Regulation
Endothelin-1 / antagonists & inhibitors,  biosynthesis,  physiology*
Interferon-gamma / metabolism
Mice
Mice, Knockout
Stress, Physiological
Sulfonamides / pharmacology
Vasoconstrictor Agents / adverse effects*
Grant Support
ID/Acronym/Agency:
//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Antigens, CD29; 0/Antihypertensive Agents; 0/Apolipoproteins E; 0/Cardiovascular Agents; 0/Endothelin-1; 0/Sulfonamides; 0/Vasoconstrictor Agents; 11128-99-7/Angiotensin II; 82115-62-6/Interferon-gamma; 9007-34-5/Collagen; Q326023R30/bosentan
Comments/Corrections

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