Endothelial Nitric Oxide Synthase–Independent Protective Action of Statin Against Angiotensin II–Induced Atrial Remodeling via Reduced Oxidant Injury

Abstract

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 Ϫ/Ϫ 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-␤1 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. (Hypertension. 2010;55:918-923.)

The influence of the atrial fibrillation episode duration on the endothelial function in patients treated with pulmonary veins isolation

“…According to current guidelines of the European Society of Cardiology, persistent AF was defined as AF episode lasting longer than 7 days or terminated by cardioversion. 9 Inclusion of the patients was limited to the cases with AF episode lasting longer than 7 days. Qualification for invasive treatment of AF was based on the guidelines of the European Society of Cardiology.…”

“…Qualification for invasive treatment of AF was based on the guidelines of the European Society of Cardiology. 9 Exclusion criteria included: neoplastic disease and persistent inflammatory state.…”

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

“…Each tissue was sectioned at 10-μm thickness and stained using fluorescent probe dihydroethidium (DHE; Molecular Probes, Oregon, USA) as previously described (Yagi et al 2010).…”

Serum Lipids and Statin Treatment During Acute Stroke

“…The effect of statins on the cerebrovascular system and the brain tissue is based on their pleiotrophic effect beyond the direct lipid effect. The vasoeffective action is based on a direct upregulation of the endothelial nitric oxide synthase (eNOS), increase of the bioavialability of NO 20-22 [Ito et al, 2010;Laufs et al, 2000;Nakata et al, 2007;Yagi et al, 2010;Ye et al, 2008;] and inhibition of NADPH oxidase [Antoniades et al, 2010;Rueckschloss et al, 2001]. This vascular effect precedes the lipid one.…”

“…The multiple mechanisms of statins on ischemic brains are based on the different targets of action. Statins increase eNOS [Ito et al, 2010;Ye et al, 2008] and reduce activity of nicotinamide adenine dinucleotide phosphate oxidase and decrease endothelin 1 and 2 and the expression of AT 1 receptor [Yagi et al, 2010]. It also acts on the inflammatory system by decreasing the nkFB [Nakata et al, 2007;Ye et al, 2008] and the expression of interleukin (IL) 1p, IL6 and MCP.…”