Modeling the mechanism of metabolic oscillations in ischemic cardiac myocytes
Modeling the mechanism of metabolic oscillations in ischemic cardiac myocytes
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DOI：
10.1016/j.jtbi.2006.05.007
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发表时间：
2006-10-21
影响因子：
2
通讯作者：
Kotulska, Malgorzata
中科院分区：
文献类型：
--
作者：
Jafri, M. Saleet;Kotulska, Malgorzata
在代谢剥夺的条件下，如缺血，在各种细胞中观察到能量代谢的振荡。在心室肌细胞中，这些代谢振荡可能导致动作电位时程振荡，在缺血期间产生心律失常的可能性（O'Rourke，2000）。本文建立了代谢振荡背后机制的数学模型。该模型包括对调节线粒体膜电位（Psi）、线粒体无机磷酸盐浓度、线粒体镁浓度以及细胞NADH和NAD（+）浓度的线粒体组分的描述。使用来自实验文献的参数，该模型在常氧（稳态）和缺血（振荡）条件下产生这些生理值。该模型包括线粒体内膜阴离子通道（IMAC）、centum picosiemen通道（mCS）、磷酸盐载体（PIC）和呼吸驱动的质子泵。该模型表明，这些都是必要的组件，用于产生振荡与mCS必不可少的快速去极化，PIC的恢复从去极化，和IMAC的去极化峰之间的缓慢去极化。由于缺血或实验条件引起的内膜电位降低似乎是振荡的触发因素。该模型模拟的实验观察，高水平的线粒体ADP和ATP废除的振荡，抑制电子传递。该模型预测pH值和镁水平对代谢振荡的影响。(c)2006爱思唯尔有限公司版权所有。
Oscillations in energy metabolism have been observed in a variety of cells under metabolically deprived conditions such as ischemia. In cardiac ventricular myocytes these metabolic oscillations may cause oscillations in the action potential duration, creating the potential for cardiac arrhythmias during ischemia (O'Rourke, 2000). A mathematical model of the mechanism behind metabolic oscillations is developed here. The model consists of descriptions of the mitochondrial components that regulate mitochondrial membrane potential (Psi), mitochondrial inorganic phosphate concentration, mitochondrial magnesium concentration, and cellular NADH and NAD(+) concentrations. Using parameters from the experimental literature, the model produces physiological values for these both under normoxic (steady state) and ischemic (oscillatory) conditions. The model includes the mitochondrial inner membrane anion channel (IMAC), the centum picosiemen channel (mCS), the phosphate carrier (PIC), and the respiration driven proton pumps. The model suggests that these are the essential components for producing oscillations with mCS essential for the rapid depolarization, PIC for the recovery from depolarization, and IMAC for the slow depolarization between depolarization peaks. A decrease of the inner membrane potential due to ischemia or experimental conditions seems to be a triggering factor for the oscillations. The model simulates the experimental observations that high levels of mitochondrial ADP and ATP abolish the oscillations, as does inhibition of electron transport. The model makes predictions on the influence of pH and magnesium levels on metabolic oscillations. (c) 2006 Elsevier Ltd. All rights reserved.