Tong Maoqing, Wang Jiewen, Ji Yunxin, Chen Xiaomin, Wang Jieru, Wang Shuangshuang, Ruan Liemin, Cui Hanbin, Zhou Ying, Zhang Qingyu, Watanabe Eiichi
Department of Cardiology, Key Laboratory of Molecular Medicine, The Affiliated Ningbo First Hospital, School of Medicine, Ningbo University, Ningbo, Zhejiang 315010, P.R. China.
Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233040, P.R. China.
Exp Ther Med. 2017 Sep;14(3):2310-2316. doi: 10.3892/etm.2017.4741. Epub 2017 Jul 9.
Atrial remodeling is considered to be any persistent change in atrial structure or function, and is responsible for the development and perpetuation of atrial fibrillation (AF). Oxidative stress and intracellular pH regulation may also be linked to AF; however it remains unclear whether eicosapentaenoic acid (EPA) or statins have beneficial therapeutic effects. The aim of the present study was to investigate the effects of EPA and pitavastatin on the electrophysiology of and gene expressions in mice with rapidly-paced atria. Mice were treated with EPA (10 mg/g/day) or pitavastatin (30 ng/g/day) for 6 weeks, following which AF was simulated by 8-h atrial pacing at 1,800 bpm. The atrial electrophysiological properties and the expression of cardiac genes, potassium voltage-gated channel subfamily A member 5 (Kcna5), Kcn subfamily D member 2 (Kcnd2), Kv channel-interacting protein 2 (KChIP2), solute carrier family 9 member A1, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI) were examined using reverse transcription-quantitative polymerase chain reaction. In control mice, significant atrial electrical remodeling was observed (P<0.05); however, treatment with either EPA or pitavastatin ameliorated these electrophysiological changes (P>0.05). mRNA levels of Kcnd2, KChIP2 and Kcna5 were significantly upregulated in control mice (P<0.05), whereas treatment with EPA or pitavastatin attenuated this upregulation (P>0.05). Administration of pitavastatin significantly reduced the downregulation of both TFPI and TM (P<0.05). EPA treatment attenuated the TFPI downregulation compared with control mice (P>0.05), however no significant effect on TM expression was observed. In addition, both EPA (P>0.05) and pitavastatin (P<0.05) suppressed the overexpression of endothelial nitric oxide synthase. This was also exhibited in Ras-related C3 botulinum toxin substrate 1 genes (P<0.01 for both treatments). In conclusion, the results of the present study suggested that EPA and pitavastatin are able to prevent atrial electrical remodeling, thrombotic states and oxidative stress in rapidly-paced murine atria.
心房重构被认为是心房结构或功能的任何持续性改变，并且是心房颤动（AF）发生和持续存在的原因。氧化应激和细胞内pH调节也可能与AF有关；然而，二十碳五烯酸（EPA）或他汀类药物是否具有有益的治疗效果仍不清楚。本研究的目的是探讨EPA和匹伐他汀对快速起搏心房小鼠的电生理和基因表达的影响。小鼠用EPA（10mg/g/天）或匹伐他汀（30ng/g/天）治疗六周，之后通过以1800次/分钟的频率进行8小时心房起搏来模拟AF。使用逆转录定量聚合酶链反应检测心房电生理特性以及心脏基因钾电压门控通道亚家族A成员5（Kcna5）、Kcn亚家族D成员2（Kcnd2）、Kv通道相互作用蛋白2（KChIP2）、溶质载体家族9成员A1、血栓调节蛋白（TM）和组织因子途径抑制剂（TFPI）的表达。在对照小鼠中，观察到明显的心房电重构（P<0.05）；然而，EPA或匹伐他汀治疗改善了这些电生理变化（P>0.05）。对照小鼠中Kcnd2、KChIP2和Kcna5的mRNA水平显著上调（P<0.05），而EPA或匹伐他汀治疗减弱了这种上调（P>0.05）。给予匹伐他汀显著降低了TFPI和TM的下调（P<0.05）。与对照小鼠相比，EPA治疗减弱了TFPI的下调（P>0.05），然而未观察到对TM表达的显著影响。此外，EPA（P>0.05）和匹伐他汀（P<0.05）均抑制了内皮型一氧化氮合酶的过表达。这在Ras相关C3肉毒杆菌毒素底物1基因中也有表现（两种治疗均为P<0.01）。总之，本研究结果表明，EPA和匹伐他汀能够预防快速起搏小鼠心房中的心房电重构、血栓形成状态和氧化应激。
