Foteinou Panagiota T, Greenstein Joseph L, Winslow Raimond L
Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
Biophys J. 2015 Aug 18;109(4):838-49. doi: 10.1016/j.bpj.2015.06.064.
Oxidative stress and calcium (Ca(2+))/calmodulin (CaM)-dependent protein kinase II (CaMKII) both play important roles in the pathogenesis of cardiac disease. Although the pathophysiological relevance of reactive oxygen species (ROS) and CaMKII has been appreciated for some time, recent work has shown that ROS can directly oxidize CaMKII, leading to its persistent activity and an increase of the likelihood of cellular arrhythmias such as early afterdepolarizations (EADs). Because CaMKII modulates the function of many proteins involved in excitation-contraction coupling, elucidation of its role in cardiac function, in both healthy and oxidative stress conditions, is challenging. To investigate this role, we have developed a model of CaMKII activation that includes both the phosphorylation-dependent and the newly identified oxidation-dependent activation pathways. This model is incorporated into our previous local-control model of the cardiac myocyte that describes excitation-contraction coupling via stochastic simulation of individual Ca(2+) release units and CaMKII-mediated phosphorylation of L-type Ca(2+) channels (LCCs), ryanodine receptors and sodium (Na(+)) channels. The model predicts the experimentally measured slow-rate dependence of H2O2-induced EADs. Upon increased H2O2, simulations suggest that selective activation of late Na(+) current (INaL), although it prolongs action potential duration, is not by itself sufficient to produce EADs. Similar results are obtained if CaMKII effects on LCCs and ryanodine receptors are considered separately. However, EADs emerge upon simultaneous activation of both LCCs and Na(+) channels. Further modeling results implicate activation of the Na(+)-Ca(2+) exchanger (NCX) as an important player in the generation of EADs. During bradycardia, the emergence of H2O2-induced EADs was correlated with a shift in the timing of NCX current reversal toward the plateau phase earlier in the action potential. Using the timing of NCX current reversal as an indicator event for EADs, the model identified counterintuitive ionic changes-difficult to experimentally dissect-that have the greatest influence on ROS-related arrhythmia propensity.
氧化应激和钙（Ca(2+)）/钙调蛋白（CaM）依赖性蛋白激酶II（CaMKII）在心脏疾病的发病机制中均起重要作用。尽管活性氧（ROS）和CaMKII的病理生理相关性已被认识一段时间，但最近的研究表明，ROS可直接氧化CaMKII，导致其持续活性增加以及细胞心律失常（如早期后去极化，EADs）发生的可能性增加。由于CaMKII调节许多参与兴奋 - 收缩偶联的蛋白质的功能，因此阐明其在健康和氧化应激条件下对心脏功能的作用具有挑战性。为了研究这一作用，我们开发了一种CaMKII激活模型，该模型包括磷酸化依赖性和新发现的氧化依赖性激活途径。该模型被纳入我们先前的心肌细胞局部控制模型中，该模型通过对单个Ca(2+)释放单元的随机模拟以及CaMKII介导的L型Ca(2+)通道（LCCs）、兰尼碱受体和钠（Na(+)）通道的磷酸化来描述兴奋 - 收缩偶联。该模型预测了实验测量的H2O2诱导的EADs的慢速率依赖性。在H2O2增加时，模拟表明晚期Na(+)电流（INaL）的选择性激活虽然延长了动作电位持续时间，但本身不足以产生EADs。如果分别考虑CaMKII对LCCs和兰尼碱受体的影响，也会得到类似的结果。然而，当LCCs和Na(+)通道同时激活时，EADs就会出现。进一步的建模结果表明，钠 - 钙交换体（NCX）的激活是EADs产生的重要因素。在心动过缓期间，H2O2诱导的EADs的出现与NCX电流反转时间向动作电位早期平台期的偏移相关。使用NCX电流反转时间作为EADs的指示事件，该模型确定了对ROS相关心律失常倾向影响最大的违反直觉的离子变化——这些变化难以通过实验进行剖析。
