Document Detail


Chronic urotensin II infusion enhances macrophage foam cell formation and atherosclerosis in apolipoprotein E-knockout mice.
MedLine Citation:
PMID:  18806619     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Our recent studies have indicated that urotensin II, the most potent vasoconstrictor peptide identified to date, potentiates human macrophage foam cell formation and vascular smooth muscle cell proliferation, and its levels are increased in the plasma of hypertensive patients with carotid atherosclerotic plaques. In the present study, we investigated the enhancing effect of urotensin II on atherosclerosis in apolipoprotein E-knockout mice and its suppression by 4-aminoquinoline, an urotensin II receptor-selective antagonist. METHODS: Urotensin II, urotensin II + 4-aminoquinoline, or vehicle was infused for 4 weeks through an osmotic mini-pump into 9-week-old apolipoprotein E-knockout mice on a high-fat diet. Aortic atherosclerosis and foam cell formation in exudate peritoneal macrophages were examined. RESULTS: Atherosclerotic lesions as well as plasma levels of urotensin II, reactive oxygen species, and oxidized low-density lipoprotein and oxidized low-density lipoprotein-induced foam cell formation were significantly greater in urotensin II-infused mice than vehicle-infused controls. Western blotting analysis showed increased expression of scavenger receptors (CD36 and scavenger receptor class A) and acyl-CoA:cholesterol acyltransferase-1 in these macrophages. Increases in these parameters were significantly reduced by addition of 4-aminoquinoline. In apolipoprotein E-knockout mice even without urotensin II infusion, the treatment with 4-aminoquinoline for 8 weeks significantly prevented the development of atherosclerotic lesions. CONCLUSION: Our results provide the first evidence that increased plasma urotensin II level stimulates oxidized low-density lipoprotein and reactive oxygen species production and macrophage foam cell formation via increased expression of CD36, scavenger receptor class A, and acyl-CoA:cholesterol acyltransferase-1, contributing to the development of atherosclerosis in apolipoprotein E-deficient mice. Urotensin II receptor antagonism may be a promising therapeutic strategy against atherosclerosis.
Authors:
Yuji Shiraishi; Takuya Watanabe; Toshiaki Suguro; Masaharu Nagashima; Rina Kato; Shigeki Hongo; Hiroyuki Itabe; Akira Miyazaki; Tsutomu Hirano; Mitsuru Adachi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of hypertension     Volume:  26     ISSN:  0263-6352     ISO Abbreviation:  J. Hypertens.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-09-22     Completed Date:  2008-12-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8306882     Medline TA:  J Hypertens     Country:  England    
Other Details:
Languages:  eng     Pagination:  1955-65     Citation Subset:  IM    
Affiliation:
First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD36 / metabolism
Apolipoproteins E / genetics
Atherosclerosis / physiopathology*
Diet, Atherogenic
Foam Cells / physiology*
Lipoproteins, LDL / metabolism
Male
Mice
Mice, Knockout
Reactive Oxygen Species / metabolism
Scavenger Receptors, Class A / metabolism
Sterol O-Acyltransferase / metabolism
Urotensins / physiology*
Chemical
Reg. No./Substance:
0/Antigens, CD36; 0/Apolipoproteins E; 0/Lipoproteins, LDL; 0/Reactive Oxygen Species; 0/Scavenger Receptors, Class A; 0/Urotensins; 0/oxidized low density lipoprotein; 9047-55-6/urotensin II; EC 2.3.1.26/Sterol O-Acyltransferase; EC 2.3.1.26/sterol O-acyltransferase 1

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