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Cardiomyocyte Na+ and Ca2+ mishandling drives vicious cycle involving CaMKII, ROS, and ryanodine receptors
Basic Research in Cardiology ( IF 9.5 ) Pub Date : 2021-10-14 , DOI: 10.1007/s00395-021-00900-9
Bence Hegyi 1 , Risto-Pekka Pölönen 1, 2 , Kim T Hellgren 1 , Christopher Y Ko 1 , Kenneth S Ginsburg 1 , Julie Bossuyt 1 , Mark Mercola 2 , Donald M Bers 1
Affiliation  

Cardiomyocyte Na+ and Ca2+ mishandling, upregulated Ca2+/calmodulin-dependent kinase II (CaMKII), and increased reactive oxygen species (ROS) are characteristics of various heart diseases, including heart failure (HF), long QT (LQT) syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). These changes may form a vicious cycle of positive feedback to promote cardiac dysfunction and arrhythmias. In HF rabbit cardiomyocytes investigated in this study, the inhibition of CaMKII, late Na+ current (INaL), and leaky ryanodine receptors (RyRs) all attenuated the prolongation and increased short-term variability (STV) of action potential duration (APD), but in age-matched controls these inhibitors had no or minimal effects. In control cardiomyocytes, we enhanced RyR leak (by low [caffeine] plus isoproterenol mimicking CPVT) which markedly increased STV and delayed afterdepolarizations (DADs). These proarrhythmic changes were significantly attenuated by both CaMKII inhibition and mitochondrial ROS scavenging, with a slight synergy with INaL inhibition. Inducing LQT by elevating INaL (by Anemone toxin II, ATX-II) caused markedly prolonged APD, increased STV, and early afterdepolarizations (EADs). Those proarrhythmic ATX-II effects were largely attenuated by mitochondrial ROS scavenging, and partially reduced by inhibition of CaMKII and pathological leaky RyRs using dantrolene. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) bearing LQT3 mutation SCN5A N406K, dantrolene significantly attenuated cell arrhythmias and APD prolongation. Targeting critical components of the Na+–Ca2+–CaMKII–ROS–INaL arrhythmogenic vicious cycle may exhibit important on-target and also trans-target effects (e.g., INaL and RyR inhibition can alter INaL-mediated LQT3 effects). Incorporating this vicious cycle into therapeutic strategies provides novel integrated insight for treating cardiac arrhythmias and diseases.



中文翻译:

心肌细胞 Na+ 和 Ca2+ 处理不当导致涉及 CaMKII、ROS 和兰尼碱受体的恶性循环

心肌细胞 Na +和 Ca 2+处理不当、Ca 2+ /钙调蛋白依赖性激酶 II (CaMKII) 上调和活性氧 (ROS) 增加是各种心脏病的特征,包括心力衰竭 (HF)、长 QT (LQT)综合征和儿茶酚胺能多形性室性心动过速 (CPVT)。这些变化可能形成正反馈的恶性循环,促进心功能不全和心律失常。在本研究中研究的 HF 兔心肌细胞中,抑制 CaMKII、晚期 Na +电流 ( I NaL) 和渗漏兰尼碱受体 (RyRs) 都减弱了动作电位持续时间 (APD) 的延长和短期变异性 (STV) 的增加,但在年龄匹配的对照中,这些抑制剂没有或只有很小的影响。在对照心肌细胞中,我们增强了 RyR 渗漏(通过低 [咖啡因] 加异丙肾上腺素模拟 CPVT),这显着增加了 STV 并延迟了后去极化 (DAD)。这些致心律失常的变化被 CaMKII 抑制和线粒体 ROS 清除显着减弱,与I NaL抑制有轻微的协同作用。通过提高I NaL诱导 LQT(通过海葵毒素 II,ATX-II)引起显着延长的 APD、增加的 STV 和早期后去极化 (EAD)。那些致心律失常的 ATX-II 效应在很大程度上被线粒体 ROS 清除所减弱,并通过使用丹曲林抑制 CaMKII 和病理性渗漏 RyRs 而部分减弱。在带有 LQT3 突变 SCN5A N406K 的人诱导多能干细胞衍生心肌细胞 (hiPSC-CM) 中,丹曲林显着减弱细胞心律失常和 APD 延长。靶向 Na + –Ca 2+ –CaMKII–ROS– I NaL致心律失常恶性循环的关键成分可能表现出重要的标效应和靶效应(例如,I NaL和 RyR 抑制可以改变NaL导的 LQT3 效应)。将这种恶性循环纳入治疗策略为治疗心律失常和疾病提供了新的综合见解。

更新日期:2021-10-15
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