Mechanisms of spontaneous Ca2+ release-mediated arrhythmia in a novel 3D human atrial myocyte model: II. Ca2+ -handling protein variation.
Mechanisms of spontaneous Ca2+ release-mediated arrhythmia in a novel 3D human atrial myocyte model: II. Ca2+ -handling protein variation.
复制标题
新型 3D 人心房肌细胞模型中自发 Ca2 释放介导的心律失常的机制：II。
DOI：
10.1113/jp283602
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Grandi,Eleonora
中科院分区：
文献类型：
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作者：
Zhang,Xianwei;Smith,CharlotteER;Morotti,Stefano;Edwards,AndrewG;Sato,Daisuke;Louch,WilliamE;Ni,Haibo;Grandi,Eleonora
心脏衰竭和房颤等疾病中横轴小管系统（TATS）的破坏与关键Ca2+处理蛋白的表达和分布变化相结合。这种超微结构和离子重塑与异常的Ca2+循环和电生理学不稳定性相关，这些都是脑电活动的基础。然而，由于疾病中TAT和Ca2+处理蛋白表达和定位的同时变化，很难区分它们对致瘤状态的单独贡献。为了研究这一点，我们应用我们的新的三维人心房肌细胞模型与空间上详细的Ca2+扩散和TATS，以研究关键Ca2+处理蛋白的表达和定位的变化和可变TATS密度对Ca2+处理异常驱动的膜不稳定性的孤立和相互作用的影响。我们发现，调节钠钙交换器、兰尼碱受体和肌浆网（SR）Ca2+缓冲钙螯合蛋白的表达和分布具有不同的促和抗心律失常作用，这取决于SR Ca2+漏负荷和Ca2+电压关系的相反影响的平衡。有趣的是，蛋白质重塑对Ca2+驱动的促凋亡行为的影响根据TATS密度的不同而变化很大，与去微管和密集微管的肌细胞相比，中度微管细胞受到的影响更严重。这项工作为TATS和Ca2+处理蛋白质重塑的独特和相互作用的后果提供了新的机制见解，TATS和Ca2+处理蛋白质重塑是疾病中功能失调的Ca2+循环和电生理不稳定性的基础。将电生理学和Ca2+处理与横轴小管系统（TATS）控制的亚细胞空间细节相结合在这里，我们利用这个模型来机械地检查TATS损失和已知在疾病中重塑的关键Ca2+处理蛋白的表达和分布的变化对Ca2+的影响。我们证明，改变这些蛋白质的表达和定位具有可变的促和抗肿瘤作用，结果显示依赖于TATS密度：而去微管的肌细胞通常表现为不受影响，而密集微管的细胞似乎受到保护，Ca2+处理蛋白重塑的促凋亡作用在中间小管细胞中是深远的。我们的工作显示了TATS和Ca2+处理蛋白重塑之间的相互作用，这是Ca2+调控的基础。在心房颤动中观察到的驱动性促心律失常行为，可能有助于预测抗心律失常策略在不同阶段的影响。超微结构重塑。
AbstractDisruption of the transverse‐axial tubule system (TATS) in diseases such as heart failure and atrial fibrillation occurs in combination with changes in the expression and distribution of key Ca2+‐handling proteins. Together this ultrastructural and ionic remodelling is associated with aberrant Ca2+cycling and electrophysiological instabilities that underlie arrhythmic activity. However, due to the concurrent changes in TATs and Ca2+‐handling protein expression and localization that occur in disease it is difficult to distinguish their individual contributions to the arrhythmogenic state. To investigate this, we applied our novel 3D human atrial myocyte model with spatially detailed Ca2+diffusion and TATS to investigate the isolated and interactive effects of changes in expression and localization of key Ca2+‐handling proteins and variable TATS density on Ca2+‐handling abnormality driven membrane instabilities. We show that modulating the expression and distribution of the sodium–calcium exchanger, ryanodine receptors and the sarcoplasmic reticulum (SR) Ca2+buffer calsequestrin have varying pro‐ and anti‐arrhythmic effects depending on the balance of opposing influences on SR Ca2+leak–load and Ca2+–voltage relationships. Interestingly, the impact of protein remodelling on Ca2+‐driven proarrhythmic behaviour varied dramatically depending on TATS density, with intermediately tubulated cells being more severely affected compared to detubulated and densely tubulated myocytes. This work provides novel mechanistic insight into the distinct and interactive consequences of TATS and Ca2+‐handling protein remodelling that underlies dysfunctional Ca2+cycling and electrophysiological instability in disease.Key pointsIn our companion paper we developed a 3D human atrial myocyte model, coupling electrophysiology and Ca2+handling with subcellular spatial details governed by the transverse‐axial tubule system (TATS).Here we utilize this model to mechanistically examine the impact of TATS loss and changes in the expression and distribution of key Ca2+‐handling proteins known to be remodelled in disease on Ca2+homeostasis and electrophysiological stability.We demonstrate that varying the expression and localization of these proteins has variable pro‐ and anti‐arrhythmic effects with outcomes displaying dependence on TATS density.Whereas detubulated myocytes typically appear unaffected and densely tubulated cells seem protected, the arrhythmogenic effects of Ca2+handling protein remodelling are profound in intermediately tubulated cells.Our work shows the interaction between TATS and Ca2+‐handling protein remodelling that underlies the Ca2+‐driven proarrhythmic behaviour observed in atrial fibrillation and may help to predict the effects of antiarrhythmic strategies at varying stages of ultrastructural remodelling.