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Abstract：
Background Oxidative stress-mediated Ca2+/calmodulin-dependent protein kinase II (Ca MKII) phosphorylation of cardiac ion channels has emerged as a critical contributor to arrhythmogenesis in cardiac pathology. However, the link between mitochondrial-derived reactive oxygen species (md ROS ) and increased Ca MKII activity in the context of cardiac arrhythmias has not been fully elucidated and is difficult to establish experimentally. Methods and Results We hypothesize that pathological md ROS can cause erratic action potentials through the oxidation-dependent Ca MKII activation pathway. We further propose that Ca MKII -dependent phosphorylation of sarcolemmal slow Na+ channels alone is sufficient to elicit early afterdepolarizations. To test the hypotheses, we expanded our well-established guinea pig cardiomyocyte excitation- contraction coupling, mitochondrial energetics, and ROS - induced- ROS - release model by incorporating oxidative Ca MKII activation and Ca MKII -dependent Na+ channel phosphorylation in silico. Simulations show that md ROS mediated-Ca MKII activation elicits early afterdepolarizations by augmenting the late Na+ currents, which can be suppressed by blocking L-type Ca2+ channels or Na+/Ca2+ exchangers. Interestingly, we found that oxidative Ca MKII activation-induced early afterdepolarizations are sustained even after md ROS has returned to its physiological levels. Moreover, mitochondrial-targeting antioxidant treatment can suppress the early afterdepolarizations, but only if given in an appropriate time window. Incorporating concurrent md ROS -induced ryanodine receptors activation further exacerbates the proarrhythmogenic effect of oxidative Ca MKII activation. Conclusions We conclude that oxidative Ca MKII activation-dependent Na channel phosphorylation is a critical pathway in mitochondria-mediated cardiac arrhythmogenesis.
摘要：
背景氧化应激介导的Ca2+/钙调蛋白依赖性蛋白激酶II(CaMKII)心脏离子通道的磷酸化已成为心脏病理学中心律失常发生的关键促成因素。然而,线粒体来源的活性氧（mdROS）与心律失常中CaMKII活性增加之间的联系尚未完全阐明，并且难以通过实验确定。方法和结果我们假设病理性mdROS可以通过氧化依赖性CaMKII激活途径引起不稳定的动作电位。我们进一步提出，仅肌膜慢Na通道的CaMKII依赖性磷酸化就足以引起早期去极化。为了测试假设，我们扩展了我们公认的豚鼠心肌细胞兴奋-收缩耦合，线粒体能量学，和ROS诱导的ROS释放模型，通过在计算机上结合氧化CaMKII激活和CaMKII依赖性Na通道磷酸化。模拟表明，mdROS介导的CaMKII激活通过增加晚期Na电流而引起早期的去极化，可以通过阻断L型Ca2通道或Na/Ca2交换剂来抑制。有趣的是,我们发现，即使在mdROS恢复到其生理水平后，氧化CaMKII活化诱导的早期去极化仍可持续。此外，线粒体靶向抗氧化剂治疗可以抑制早期的去极化，但前提是在适当的时间窗口中给出。合并并发mdROS诱导的ryanodine受体激活进一步加剧了氧化CaMKII激活的致心律失常作用。结论我们得出结论，氧化CaMKII激活依赖性Na通道磷酸化是线粒体介导的心律失常发生的关键途径。
