Bagci Elife Z, Vodovotz Yoram, Billiar Timothy R, Ermentrout Bard, Bahar Ivet
Department of Computational Biology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS One. 2008 May 28;3(5):e2249. doi: 10.1371/journal.pone.0002249.
Despite the establishment of the important role of nitric oxide (NO) on apoptosis, a molecular-level understanding of the origin of its dichotomous pro- and anti-apoptotic effects has been elusive. We propose a new mathematical model for simulating the effects of nitric oxide (NO) on apoptosis. The new model integrates mitochondria-dependent apoptotic pathways with NO-related reactions, to gain insights into the regulatory effect of the reactive NO species N(2)O(3), non-heme iron nitrosyl species (FeL(n)NO), and peroxynitrite (ONOO(-)). The biochemical pathways of apoptosis coupled with NO-related reactions are described by ordinary differential equations using mass-action kinetics. In the absence of NO, the model predicts either cell survival or apoptosis (a bistable behavior) with shifts in the onset time of apoptotic response depending on the strength of extracellular stimuli. Computations demonstrate that the relative concentrations of anti- and pro-apoptotic reactive NO species, and their interplay with glutathione, determine the net anti- or pro-apoptotic effects at long time points. Interestingly, transient effects on apoptosis are also observed in these simulations, the duration of which may reach up to hours, despite the eventual convergence to an anti-apoptotic state. Our computations point to the importance of precise timing of NO production and external stimulation in determining the eventual pro- or anti-apoptotic role of NO.
尽管一氧化氮（NO）在细胞凋亡中的重要作用已得到确立，但对其促凋亡和抗凋亡二分效应起源的分子水平理解仍难以捉摸。我们提出了一种新的数学模型来模拟一氧化氮（NO）对细胞凋亡的影响。新模型将线粒体依赖性凋亡途径与NO相关反应整合在一起，以深入了解活性NO物质N(2)O(3)、非血红素铁亚硝酰基物质（FeL(n)NO）和过氧亚硝酸盐（ONOO(-)）的调节作用。细胞凋亡的生化途径与NO相关反应通过使用质量作用动力学的常微分方程来描述。在没有NO的情况下，该模型预测细胞存活或凋亡（双稳态行为），凋亡反应起始时间的变化取决于细胞外刺激的强度。计算表明，抗凋亡和促凋亡活性NO物质的相对浓度及其与谷胱甘肽的相互作用，在长时间点决定了净抗凋亡或促凋亡效应。有趣的是，在这些模拟中也观察到了对细胞凋亡的瞬时效应，尽管最终会收敛到抗凋亡状态，但其持续时间可能长达数小时。我们的计算指出了NO产生的精确时间和外部刺激在确定NO最终促凋亡或抗凋亡作用方面的重要性。
