Section of Cardiology and Center for Cardiovascular Research, University of Illinois at Chicago, IL, USA.
Circ Arrhythm Electrophysiol. 2013 Jun;6(3):623-31. doi: 10.1161/CIRCEP.112.976787. Epub 2013 Apr 4.
Previously, we showed that a mouse model (ACE8/8) of cardiac renin-angiotensin system activation has a high rate of spontaneous ventricular tachycardia and sudden cardiac death secondary to a reduction in connexin43 level. Angiotensin-II activation increases reactive oxygen species (ROS) production, and ACE8/8 mice show increased cardiac ROS. We sought to determine the source of ROS and whether ROS played a role in the arrhythmogenesis.
Wild-type and ACE8/8 mice with and without 2 weeks of treatment with L-NIO (NO synthase inhibitor), sepiapterin (precursor of tetrahydrobiopterin), MitoTEMPO (mitochondria-targeted antioxidant), TEMPOL (a general antioxidant), apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor), allopurinol (xanthine oxidase inhibitor), and ACE8/8 crossed with P67 dominant negative mice to inhibit the nicotinamide adenine dinucleotide phosphate oxidase were studied. Western blotting, detection of mitochondrial ROS by MitoSOX Red, electron microscopy, immunohistochemistry, fluorescent dye diffusion technique for functional assessment of connexin43, telemetry monitoring, and in vivo electrophysiology studies were performed. Treatment with MitoTEMPO reduced sudden cardiac death in ACE8/8 mice (from 74% to 18%; P<0.005), decreased spontaneous ventricular premature beats, decreased ventricular tachycardia inducibility (from 90% to 17%; P<0.05), diminished elevated mitochondrial ROS to the control level, prevented structural damage to mitochondria, resulted in 2.6-fold increase in connexin43 level at the gap junctions, and corrected gap junction conduction. None of the other antioxidant therapies prevented ventricular tachycardia and sudden cardiac death in ACE8/8 mice.
Mitochondrial oxidative stress plays a central role in angiotensin II-induced gap junction remodeling and arrhythmia. Mitochondria-targeted antioxidants may be effective antiarrhythmic drugs in cases of renin-angiotensin system activation.
此前，我们发现心脏肾素-血管紧张素系统激活的 ACE8/8 小鼠模型存在自发性室性心动过速和心脏性猝死的高发生率，这与连接蛋白 43 水平降低有关。血管紧张素-II 的激活增加了活性氧（ROS）的产生，ACE8/8 小鼠表现出心脏 ROS 的增加。我们试图确定 ROS 的来源以及 ROS 是否在心律失常的发生中发挥作用。
研究了野生型和 ACE8/8 小鼠，以及接受 2 周 L-NIO（一氧化氮合酶抑制剂）、六氢生物蝶呤（四氢生物蝶呤前体）、MitoTEMPO（线粒体靶向抗氧化剂）、TEMPOL（一般抗氧化剂）、apocynin（烟酰胺腺嘌呤二核苷酸磷酸氧化酶抑制剂）、allopurinol（黄嘌呤氧化酶抑制剂）和 ACE8/8 与 P67 显性负性小鼠交叉以抑制烟酰胺腺嘌呤二核苷酸磷酸氧化酶治疗的小鼠。进行了 Western blot 分析、MitoSOX Red 检测线粒体 ROS、电子显微镜检查、免疫组织化学、荧光染料扩散技术评估连接蛋白 43 的功能、遥测监测和体内电生理学研究。MitoTEMPO 治疗降低了 ACE8/8 小鼠的心脏性猝死发生率（从 74%降至 18%；P<0.005），减少了自发性室性早搏，降低了室性心动过速的诱导率（从 90%降至 17%；P<0.05），降低了升高的线粒体 ROS 至对照水平，防止了线粒体的结构损伤，导致缝隙连接处的连接蛋白 43 水平增加 2.6 倍，并纠正了缝隙连接的传导。其他抗氧化治疗均不能预防 ACE8/8 小鼠的室性心动过速和心脏性猝死。
线粒体氧化应激在血管紧张素 II 诱导的缝隙连接重构和心律失常中起核心作用。线粒体靶向抗氧化剂可能是肾素-血管紧张素系统激活病例中的有效抗心律失常药物。
