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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Role of CaMKII in post acidosis arrhythmias: a simulation study using a human myocyte model.
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Role of CaMKII in post acidosis arrhythmias: a simulation study using a human myocyte model.

机译：CaMKII在酸中毒后心律失常中的作用：使用人类心肌细胞模型的模拟研究。

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Postacidotic arrhythmias have been associated to increased sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activation. However, the molecular mechanisms underlying these arrhythmias are still unclear. To better understand this process, acidosis produced by CO2 increase from 5% to 30%, resulting in intracellular pH (pHi) change from 7.15 to 6.7, was incorporated into a myocyte model of excitation-contraction coupling and contractility, including acidotic inhibition of L-type Ca(2+) channel (I(CaL)), Na(+)-Ca(2+) exchanger, Ca(2+) release through the SR ryanodine receptor (RyR2) (I(rel)), Ca(2+) reuptake by the SR Ca(2+) ATPase2a (I(up)), Na(+)-K(+) pump, K(+) efflux through the inward rectifier K(+) channel and the transient outward K(+) flow (I(to)) together with increased activity of the Na(+)-H(+) exchanger (I(NHE)). Simulated CaMKII regulation affecting I(rel), I(up), I(CaL), I(NHE) and I(to) was introduced in the model to partially compensate the acidosis outcome. Late Na(+) current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca(2+) leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca(2+)], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis. The model showed that DADs depend on SR Ca(2+) load and on increased Ca(2+) leak through RyR2. This postacidotic arrhythmogenic pattern relies mainly on CaMKII effect on I(CaL) and I(up), since its individual elimination produced the highest DAD reduction. The model further revealed that during the return to normal pHi, DADs are fully determined by SR Ca(2+) load at the end of acidosis. Thereafter, DADs are maintained by SR Ca(2+) reloading by Ca(2+) influx through the reverse NCX mode during the time period in which [Na(+)]i is elevated.
机译：酸中毒后心律失常与肌浆网（SR）Ca（2+）负荷和Ca（2 +）/钙调蛋白依赖性蛋白激酶II（CaMKII）激活有关。然而，这些心律不齐的分子机制仍不清楚。为了更好地理解该过程，CO2产生的酸中毒从5％增加到30％，导致细胞内pH（pHi）从7.15改变为6.7，并被纳入激发-收缩偶联和收缩力的肌细胞模型，包括L对酸的抑制型Ca（2+）通道（I（CaL）），Na（+）-Ca（2+）交换剂，Ca（2+）通过SR ryanodine受体（RyR2）（I（rel））释放，Ca（ 2+）由SR Ca（2+）ATPase2a（I（up）），Na（+）-K（+）泵，通过向内整流器K（+）通道的K（+）外排和瞬态向外K （+）流量（I（to））以及Na（+）-H（+）交换剂（I（NHE））的活性增加。将影响I（rel），I（up），I（CaL），I（NHE）和I（to）的模拟CaMKII调节引入模型中，以部分补偿酸中毒的结果。 CaMKII增加的后期Na（+）电流也被纳入。使用该方案，并假设舒张压Ca（2+）通过RyR2的泄漏是由该通道的静止状态调节的，SR和二分形裂口[Ca（2+）]之间的差异，触发去酸后延迟去极化（DADs）酸中毒6分钟后恢复至正常pHi。该模型显示DAD取决于SR Ca（2+）负载和通过RyR2增加的Ca（2+）泄漏。这种酸中毒后心律失常的模式主要依赖于CaMKII对I（CaL）和I（up）的作用，因为其单独消除可产生最高的DAD降低。该模型进一步揭示，在恢复正常pHi期间，酸中毒末期的SR Ca（2+）负荷可完全确定DAD。此后，DAD由SR Ca（2+）通过[Na（+）] i升高的时间段内通过反向NCX模式通过Ca（2+）流入重新加载来维护。

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