Inhibiting Na+/K+ ATPase can impair mitochondrial energetics and induce abnormal Ca2+ cycling and automaticity in guinea pig cardiomyocytes.
Inhibiting Na+/K+ ATPase can impair mitochondrial energetics and induce abnormal Ca2+ cycling and automaticity in guinea pig cardiomyocytes.
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DOI：
10.1371/journal.pone.0093928
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhou L
中科院分区：
文献类型：
--
作者：
Li Q;Pogwizd SM;Prabhu SD;Zhou L
强心苷已被用于治疗心力衰竭，因为它们具有抑制 Na+/K+ ATP 酶 (NKA) 的能力，NKA 会升高 [Na+]i 并减弱通过 Na+/Ca2+ 交换器 (NCX) 的 Ca2+ 排出，导致 [Ca2+]i 升高。由此产生的 [Ca2+]i 积累进一步增强 Ca2+ 诱导的 Ca2+ 释放，产生正性肌力作用。然而，强心苷类药物存在心律失常等毒副作用，限制了其广泛的临床应用。苷类致心律失常作用的机制尚不完全清楚。在这里，我们使用综合计算心肌细胞模型研究了糖苷通过损害线粒体能量而导致心律失常的机制。在模拟中，通过阻断 NKA 活性来模拟糖苷的作用。结果表明，抑制 NKA 不仅会损害线粒体 Ca2+ 保留（从而抑制活性氧 (ROS) 清除），而且会在工作负荷增加的过渡过程中增强氧化磷酸化（从而增加 ROS 产生），从而引起氧化应激。此外，同时阻断线粒体Na+/Ca2+交换器，但不增强Ca2+单向转运蛋白，减轻了NKA抑制的不利影响。有趣的是，NKA 抑制在压力更大的条件下（例如严重 ATP 耗竭）引起 Ca2+ 瞬时和动作电位交替，从而增强其致心律失常作用。这项计算研究为强心苷诱导心律失常发生的机制提供了新的见解。研究结果表明，针对离子处理和线粒体可能是开发新的糖苷疗法治疗心力衰竭的非常有前途的策略。
Cardiac glycosides have been used for the treatment of heart failure because of their capabilities of inhibiting Na+/K+ ATPase (NKA), which raises [Na+]i and attenuates Ca2+ extrusion via the Na+/Ca2+ exchanger (NCX), causing [Ca2+]i elevation. The resulting [Ca2+]i accumulation further enhances Ca2+-induced Ca2+ release, generating the positive inotropic effect. However, cardiac glycosides have some toxic and side effects such as arrhythmogenesis, confining their extensive clinical applications. The mechanisms underlying the proarrhythmic effect of glycosides are not fully understood. Here we investigated the mechanisms by which glycosides could cause cardiac arrhythmias via impairing mitochondrial energetics using an integrative computational cardiomyocyte model. In the simulations, the effect of glycosides was mimicked by blocking NKA activity. Results showed that inhibiting NKA not only impaired mitochondrial Ca2+ retention (thus suppressed reactive oxygen species (ROS) scavenging) but also enhanced oxidative phosphorylation (thus increased ROS production) during the transition of increasing workload, causing oxidative stress. Moreover, concurrent blocking of mitochondrial Na+/Ca2+ exchanger, but not enhancing of Ca2+ uniporter, alleviated the adverse effects of NKA inhibition. Intriguingly, NKA inhibition elicited Ca2+ transient and action potential alternans under more stressed conditions such as severe ATP depletion, augmenting its proarrhythmic effect. This computational study provides new insights into the mechanisms underlying cardiac glycoside-induced arrhythmogenesis. The findings suggest that targeting both ion handling and mitochondria could be a very promising strategy to develop new glycoside-based therapies in the treatment of heart failure.
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影响因子：
4.3
作者：
Csordas, Gyoergy;Hajnoczky, Gyoergy
通讯作者：
Hajnoczky, Gyoergy
影响因子：
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作者：
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Winslow RL
影响因子：
20.1
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Winslow, Raimond L.
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作者：
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通讯作者：
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