Zou Deling, Geng Ning, Chen Yanli, Ren Li, Liu Xingli, Wan Jiye, Guo Sicong, Wang Shaojun
Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
Life Sci. 2016 Jul 1;156:7-14. doi: 10.1016/j.lfs.2016.05.026. Epub 2016 May 18.
Ranolazine, an antianginal agent used for chronic stable angina treatment, was demonstrated to be effective in atrial fibrillation (AF) treatment. The aim of this study was to explore the molecular mechanisms of its anti-AF effects.
AF rat model was established using acetylcholine (ACh)-CaCl2 injection for 7days followed by ACh infusion into the heart. Prior to ACh infusion, ranolazine at 10.7mg/kg/0.5ml was injected into vein and followed by 0.56mg/kg/min infusion. Blood pressure and electrocardiogram were monitored during the infusion. Histological changes of atrial tissue were observed after H&E staining. Activities and protein expression of NADPH oxidase-4, xanthine oxidase, glutathione peroxidase and superoxide dismutase were examined using commercial assay kits and Western botting, respectively. Mitochondrial functions were evaluated through membrane potential, ATP production, activities of complex I and III and reactive oxygen species production. Apoptosis was measured using TUNEL staining. Protein expression of apoptotic proteins Bcl-2, Bax and cleaved-caspase 3 and Akt/mTOR signaling proteins were detected using Western blotting.
Results demonstrated that ranolazine attenuated AF in ACh-CaCl2-exposed rats. In addition, ranolazine restored mitochondrial function, suppressed oxidative stress, and inhibited atrial cells apoptosis. Furthermore, the activated Akt/mTOR signaling pathway induced by AF was further activated by ranolazine.
The present study confirms the effects of ranolazine on AF rats induced by ACh-CaCl2, and provides evidence that the anti-AF effects are associated with the restoration of mitochondrial function and activation of the Akt/mTOR signaling pathway in atrial tissue.
雷诺嗪是一种用于治疗慢性稳定型心绞痛的抗心绞痛药物，已被证明对心房颤动（AF）治疗有效。本研究的目的是探讨其抗AF作用的分子机制。
采用乙酰胆碱（ACh）-氯化钙注射7天，随后向心脏内输注ACh建立AF大鼠模型。在输注ACh之前，将10.7mg/kg/0.5ml的雷诺嗪静脉注射，然后以0.56mg/kg/min的速度输注。输注过程中监测血压和心电图。苏木精-伊红（H&E）染色后观察心房组织的组织学变化。分别使用商业检测试剂盒和蛋白质免疫印迹法检测烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶-4、黄嘌呤氧化酶、谷胱甘肽过氧化物酶和超氧化物歧化酶的活性及蛋白表达。通过膜电位、三磷酸腺苷（ATP）生成、复合体I和III的活性以及活性氧生成评估线粒体功能。使用末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）染色法检测细胞凋亡。使用蛋白质免疫印迹法检测凋亡蛋白Bcl-2、Bax和裂解的半胱天冬酶-3以及蛋白激酶B（Akt）/哺乳动物雷帕霉素靶蛋白（mTOR）信号蛋白的表达。
结果表明，雷诺嗪可减轻ACh-氯化钙处理大鼠的AF。此外，雷诺嗪恢复了线粒体功能，抑制了氧化应激，并抑制了心房细胞凋亡。此外，AF诱导的活化Akt/mTOR信号通路被雷诺嗪进一步激活。
本研究证实了雷诺嗪对ACh-氯化钙诱导的AF大鼠的作用，并提供了证据表明其抗AF作用与心房组织中线粒体功能的恢复和Akt/mTOR信号通路的激活有关。
