Endothelial Nitric Oxide Synthase-Independent Protective Action of Statin Against Angiotensin II-Induced Atrial Remodeling via Reduced Oxidant Injury
Endothelial Nitric Oxide Synthase-Independent Protective Action of Statin Against Angiotensin II-Induced Atrial Remodeling via Reduced Oxidant Injury
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DOI：
10.1161/hypertensionaha.109.146076
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发表时间：
2010-04-01
期刊：
影响因子：
8.3
通讯作者：
Sata, Masataka
中科院分区：
文献类型：
--
作者：
Yagi, Shusuke;Akaike, Masashi;Sata, Masataka
肾素-血管紧张素系统的激活会加剧心房重构，导致心房颤动和血栓形成，特别是在生物利用度降低的情况下。近年来，有报道他汀类药物通过抑制心房重构而减少心房颤动的发生，但其机制尚未完全阐明。因此，我们的目的是阐明他汀类药物在非生物利用度降低的条件下对心房重构的有利作用。将内皮一氧化氮合酶(-/-)小鼠假手术或血管紧张素II(Ang II)经渗透压泵注入2周后，随机分为3组：匹伐他汀组、自由基清除剂Tempoll组和赋形剂组。超声心动图和心电图示Ang II输注可引起左房增大和心房颤动的高发生率，而倍他汀和坦泊尔则可阻止这些异常。在组织学分析中，血管紧张素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坦普尔减轻。免疫组织化学染色显示Ang II下调左心房血栓调节蛋白和组织因子途径抑制物，上调组织因子和纤溶酶原激活物抑制物1，匹伐他汀和坦普尔可纠正血栓形成。Pitavastatin和Tempoll还可降低Ang II诱导的心房超氧化物歧化、转化生长因子-β1表达和Smad2/3的磷酸化。已知可激活NADPH氧化酶的心房rac1-GTPase活性可被匹伐他汀减弱，但不能被Tempoll减弱。结论：匹伐他汀对血管紧张素Ⅱ诱导的心房重构和心房颤动具有不依赖于合酶的内皮保护作用，并通过抑制氧化损伤增强血栓形成能力。(高血压。2010；55：918-923。)
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-beta 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.)