title: Endothelial nitric oxide synthase-independent protective action of statin against angiotensin II-induced atrial remodeling via reduced oxidant injury.
abstract: 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.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.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Yagi
authors.forename: Masashi
authors.initials: M
authors.lastname: Akaike
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Aihara
authors.forename: Kazue
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwase
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Soeki
authors.forename: Sumiko
authors.initials: S
authors.lastname: Yoshida
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sumitomo-Ueda
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004452:Echocardiography; D005355:Fibrosis / Q000473:pathology; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*; D012084:Renin-Angiotensin System / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013113:Spin Labels; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D051899:Smad2 Protein; D051900:Smad3 Protein; D013113:Spin Labels; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D052250:Nitric Oxide Synthase Type III; C108475:pitavastatin; C001803:tempol