Department of Cardiovascular Medicine, University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Hypertension. 2010 Apr;55(4):918-23. doi: 10.1161/HYPERTENSIONAHA.109.146076. Epub 2010 Mar 1.
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.
肾素-血管紧张素系统的激活可加重心房重构，导致心房颤动和血栓形成，尤其是在一氧化氮生物利用度降低的情况下。最近，有报道称他汀类药物可通过减轻心房重构来降低心房颤动的发生率；然而，其机制尚未完全阐明。因此，我们旨在阐明他汀类药物在降低一氧化氮生物利用度的情况下对心房重构的有益作用。内皮型一氧化氮合酶（-/-）小鼠接受假手术或通过渗透微型泵输注血管紧张素 II（Ang II）2 周，Ang II 输注的小鼠分为 3 个治疗组：匹伐他汀、Tempol（自由基清除剂）或载体。超声心动图和心电图显示，Ang II 输注导致左心房扩大和心房颤动发生率升高，而匹伐他汀和 Tempol 可预防这些异常。组织学分析显示，Ang II 诱导的心房间质纤维化、血管周围纤维化和心肌细胞肥大均被匹伐他汀和 Tempol 减弱。免疫组织化学染色显示，Ang II 下调了左心房中的血栓调节蛋白和组织因子途径抑制剂，并上调了组织因子和纤溶酶原激活物抑制剂 1，而匹伐他汀和 Tempol 纠正了血栓形成状态。此外，匹伐他汀和 Tempol 减少了 Ang II 诱导的心房超氧化物产生和心房转化生长因子-β1 表达以及 Smad 2/3 磷酸化。已知激活 NADPH 氧化酶的心房 rac1-GTPase 活性被匹伐他汀减弱，但不受 Tempol 影响。综上所述，匹伐他汀通过抑制氧化应激损伤，发挥内皮型一氧化氮合酶非依赖性的保护作用，防止 Ang II 诱导的心房重构和心房颤动，并增强其血栓形成性。
