Document Detail


Endothelial nitric oxide synthase-independent protective action of statin against angiotensin II-induced atrial remodeling via reduced oxidant injury.
MedLine Citation:
PMID:  20194307     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Activation of the renin-angiotensin system exacerbates atrial remodeling, leading to atrial fibrillation and thrombosis, especially in a condition with decreased NO bioavailability. Recently, it has been reported that statins reduce the incidence of atrial fibrillation through attenuation of atrial remodeling; however, the mechanisms have not been completely elucidated. Therefore, we aimed to clarify the beneficial effect of statin on atrial remodeling in condition with reduced NO bioavailability. Endothelial NO synthase(-/-) mice were sham operated or infused with angiotensin II (Ang II) via an osmotic minipump for 2 weeks, and Ang II-infused mice were divided into 3 treatment groups: pitavastatin, Tempol (a free radical scavenger), or vehicle. Echocardiography and electrocardiography showed that Ang II infusion caused left atrial enlargement and a high incidence of atrial fibrillation, whereas pitavastatin and Tempol prevented these abnormalities. In histological analysis, Ang II-induced atrial interstitial fibrosis, perivascular fibrosis, and cardiomyocyte hypertrophy were all attenuated by pitavastatin and Tempol. Immunohistochemical staining showed that Ang II downregulated thrombomodulin and tissue factor pathway inhibitor and upregulated tissue factor and plasminogen activator inhibitor 1 in the left atrium and that pitavastatin and Tempol corrected the thrombogenic condition. Moreover, pitavastatin and Tempol reduced Ang II-induced atrial superoxide production and atrial transforming growth factor-beta1 expression and Smad 2/3 phosphorylation. Atrial rac1-GTPase activity, known to activate NADPH oxidase, was attenuated by pitavastatin but not by Tempol. In conclusion, pitavastatin exerts endothelial NO synthase-independent protective actions against Ang II-induced atrial remodeling and atrial fibrillation with enhanced thrombogenicity through suppression of oxidant injury.
Authors:
Shusuke Yagi; Masashi Akaike; Ken-ichi Aihara; Kazue Ishikawa; Takashi Iwase; Yasumasa Ikeda; Takeshi Soeki; Sumiko Yoshida; Yuka Sumitomo-Ueda; Toshio Matsumoto; Masataka Sata
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-01
Journal Detail:
Title:  Hypertension     Volume:  55     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-03-18     Completed Date:  2010-04-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  918-23     Citation Subset:  IM    
Affiliation:
Department of Cardiovascular Medicine, University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. syagi@clin.med.tokushima-u.ac.jp.
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Angiotensin II / pharmacology*
Animals
Antioxidants / pharmacology
Atrial Fibrillation / metabolism
Blood Pressure / drug effects
Blotting, Western
Cardiomegaly / metabolism,  pathology
Cyclic N-Oxides / pharmacology
Echocardiography
Fibrosis / pathology
Heart Atria / drug effects*,  metabolism,  pathology
Heart Rate / drug effects
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
Male
Mice
Mice, Knockout
Myocytes, Cardiac / drug effects,  metabolism,  pathology
Nitric Oxide Synthase Type III / genetics,  metabolism*
Oxidative Stress / drug effects*
Quinolines / pharmacology*
Renin-Angiotensin System / drug effects
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects
Smad2 Protein / metabolism
Smad3 Protein / metabolism
Spin Labels
Transforming Growth Factor beta1 / metabolism
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Cyclic N-Oxides; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Quinolines; 0/Smad2 Protein; 0/Smad3 Protein; 0/Spin Labels; 0/Transforming Growth Factor beta1; 11128-99-7/Angiotensin II; 147526-32-7/NK 104; 2226-96-2/tempol; EC 1.14.13.39/Nitric Oxide Synthase Type III

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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