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Computational insights on the competing effects of nitric oxide in regulating apoptosis

Bagci, EZ and Vodovotz, Y and Billiar, TR and Ermentrout, B and Bahar, I (2008) Computational insights on the competing effects of nitric oxide in regulating apoptosis. PLoS ONE, 3 (5).

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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 N2O3, non-heme iron nitrosyl species (FeLnNO), and peroxynitrite (ONOO-). The biochemical pathways of opoptosis 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. © 2008 Bagci et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Bagci, EZ
Vodovotz, Yvodovotz@pitt.eduVODOVOTZ
Billiar, TRbilliar@pitt.eduBILLIAR
Ermentrout, B
Bahar, Iivet.bahar@stonybrook.eduBAHAR
ContributionContributors NameEmailPitt UsernameORCID
Date: 28 May 2008
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 3
Number: 5
DOI or Unique Handle: 10.1371/journal.pone.0002249
Schools and Programs: Dietrich School of Arts and Sciences > Mathematics
School of Medicine > Biochemistry and Molecular Genetics
School of Medicine > Computational Biology
Refereed: Yes
PubMed ID: 18509469
Date Deposited: 18 Jul 2012 20:33
Last Modified: 17 Mar 2023 11:55


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