Department of Computer Science, University of Oxford, Wolfson Building, Parks Road, Oxford, OX1 3QD, UK,
Pflugers Arch. 2014 Feb;466(2):183-93. doi: 10.1007/s00424-013-1293-1. Epub 2013 May 15.
The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the systems biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most important ionic mechanisms in regulating key properties of cardiac repolarization and its rate dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies.
钠钾泵被广泛认为是心肌细胞膜主动离子转运的主要机制，负责创建和维持跨细胞层的钠钾梯度，这对心肌细胞电生理至关重要。重要的是，钠钾泵的活性在许多主要疾病中受到损害，包括缺血和心力衰竭。然而，它对心肌电生理的微妙作用方式，包括通过其电生成性质的直接作用和通过细胞内稳态的调节的间接作用，使得很难预测钠钾泵活性降低对心脏复极的电生理后果。在这篇综述中，我们讨论了最近采用系统生物学方法的研究如何通过整合实验和建模方法，将钠钾泵确定为调节心脏复极及其速率依赖性的关键特性的最重要的离子机制之一，从亚细胞到整个器官水平。这些特性包括泵在细胞复极和不应期的双相调制中的作用、细胞内钠和钙动力学的速率控制以及因此复极对心率变化的适应能力，以及通过调制复极离散度和恢复性来调节致心律失常底物的重要性。理论发现与包括人类在内的多种细胞类型和物种一致，并且与实验发现广泛一致。通过这种综合方法获得的泵在心脏电生理中的作用的新见解和假说，最终可能导致新的治疗和诊断策略。
