Cardiac Alternans Occurs through the Synergy of Voltage- and Calcium-Dependent Mechanisms.
Cardiac Alternans Occurs through the Synergy of Voltage- and Calcium-Dependent Mechanisms.
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心脏替代品通过电压和钙依赖性机制的协同作用。
DOI：
10.3390/membranes11100794
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发表时间：
2021-10-18
期刊：
影响因子：
4.2
通讯作者：
Jafri MS
中科院分区：
文献类型：
--
作者：
Hoang-Trong MT;Ullah A;Lederer WJ;Jafri MS
心脏交替的特点是心脏的强弱交替跳动。这种信号在细胞水平上可能表现为长、短动作电位（APs）交替，它们分别与大、小钙瞬变同步发生。先前的研究表明，交替表现为基于动作电位恢复的电压依赖机制或基于钙释放难熔性的钙依赖机制。我们在大鼠心室肌细胞中使用了一种新的心脏兴奋-收缩（EC）耦合模型，该模型包括20,000个钙释放单位（CRU），每个单位有49个ryanodine受体（RyR2s）和7个l型钙通道，这些通道都是随机门控的。该模型表明，在细胞水平上，在快速起搏产生交替的情况下，该机制需要电压和钙依赖机制的协同作用。快速起搏缩短了AP的持续时间和幅度，减少了每次AP期间激活单个cru的l型钙通道的数量，从而增加了随机招募的cru数量。根据我们在模拟中使用的模型，升高的肌浆和肌浆网（SR）钙，[Ca2+]myo和[Ca2+]SR分别增加了ryanodine受体打开概率（Po），这增加了激活额外cru的可能性。由于连接肌浆网（jSR）不完全充血所引起的难熔性，在一次搏动中打开的CRU不太可能打开随后的搏动。此外，该模型还包括对Na+通量和[Na+]i变化的估计，从而深入了解电活动、[Na+]i和钠钙交换器活性的变化如何调节交替。因此，该模型追踪了能够解释[Na+]i和[Ca2+]myo中速率依赖性变化的关键因素，以及它们如何促进心脏中Ca2+信号交替的产生。
Cardiac alternans is characterized by alternating weak and strong beats of the heart. This signaling at the cellular level may appear as alternating long and short action potentials (APs) that occur in synchrony with alternating large and small calcium transients, respectively. Previous studies have suggested that alternans manifests itself through either a voltage dependent mechanism based upon action potential restitution or as a calcium dependent mechanism based on refractoriness of calcium release. We use a novel model of cardiac excitation-contraction (EC) coupling in the rat ventricular myocyte that includes 20,000 calcium release units (CRU) each with 49 ryanodine receptors (RyR2s) and 7 L-type calcium channels that are all stochastically gated. The model suggests that at the cellular level in the case of alternans produced by rapid pacing, the mechanism requires a synergy of voltage- and calcium-dependent mechanisms. The rapid pacing reduces AP duration and magnitude reducing the number of L-type calcium channels activating individual CRUs during each AP and thus increases the population of CRUs that can be recruited stochastically. Elevated myoplasmic and sarcoplasmic reticulum (SR) calcium, [Ca2+]myo and [Ca2+]SR respectively, increases ryanodine receptor open probability (Po) according to our model used in this simulation and this increased the probability of activating additional CRUs. A CRU that opens in one beat is less likely to open the subsequent beat due to refractoriness caused by incomplete refilling of the junctional sarcoplasmic reticulum (jSR). Furthermore, the model includes estimates of changes in Na+ fluxes and [Na+]i and thus provides insight into how changes in electrical activity, [Na+]i and sodium-calcium exchanger activity can modulate alternans. The model thus tracks critical elements that can account for rate-dependent changes in [Na+]i and [Ca2+]myo and how they contribute to the generation of Ca2+ signaling alternans in the heart.
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影响因子：
20.1
作者：
Brette, F;Orchard, CH
通讯作者：
Orchard, CH
影响因子：
5.5
作者：
Blatter, LA;Kockskämper, J;Lipsius, SL
通讯作者：
Lipsius, SL
影响因子：
20.1
作者：
Aistrup, Gary L.;Kelly, James E.;Wasserstrom, J. Andrew
通讯作者：
Wasserstrom, J. Andrew
DOI：
10.1152/ajpheart.00612.2001
发表时间：
2002-02-01
影响因子：
4.8
作者：
Fox, JJ;McHarg, JL;Gilmour, RF
通讯作者：
Gilmour, RF
影响因子：
20.1
作者：
Aistrup, Gary L.;Shiferaw, Yohannes;Wasserstrom, J. Andrew
通讯作者：
Wasserstrom, J. Andrew