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

Bagci EZ, Vodovotz Y, Billiar TR, Ermentrout B, Bahar I - PLoS ONE (2008)

Bottom Line: We propose a new mathematical model for simulating the effects of nitric oxide (NO) on apoptosis.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Biology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
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.

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Related in: MedlinePlus

Time evolutions of A) GSH, B) N2O3, C) FeLnNO, and D) ONOO− predicted by Model II.N2O3 and FeLnNO increase to high concentrations by a switch-like mechanism induced by a decrease in GSH concentration due to conversion of GSH to GSNO and subsequently to GSSG. [ONOO−] does not follow a similar switch-like increase in its concentration. Solid curve is for [GSH]0 = 104 µM, dotted curve for [GSH]0 = 103 µM, and dashed curve with diamonds for [GSH]0 = 102 µM. The response is thus sharper and earlier in the presence of lower initial concentrations of GSH.
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pone-0002249-g003: Time evolutions of A) GSH, B) N2O3, C) FeLnNO, and D) ONOO− predicted by Model II.N2O3 and FeLnNO increase to high concentrations by a switch-like mechanism induced by a decrease in GSH concentration due to conversion of GSH to GSNO and subsequently to GSSG. [ONOO−] does not follow a similar switch-like increase in its concentration. Solid curve is for [GSH]0 = 104 µM, dotted curve for [GSH]0 = 103 µM, and dashed curve with diamonds for [GSH]0 = 102 µM. The response is thus sharper and earlier in the presence of lower initial concentrations of GSH.

Mentions: The results from our calculations using Model II are shown in Figure 3. Here, we focused on the time evolution of four compounds, GSH, N2O3, FeLnNO and ONOO−, displayed in respective panels A–D. The NO species N2O3, FeLnNO and ONOO− have been proposed to carry out various indirect effects of NO on cellular pathways, including apoptosis, during inflammation [20].


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

Bagci EZ, Vodovotz Y, Billiar TR, Ermentrout B, Bahar I - PLoS ONE (2008)

Time evolutions of A) GSH, B) N2O3, C) FeLnNO, and D) ONOO− predicted by Model II.N2O3 and FeLnNO increase to high concentrations by a switch-like mechanism induced by a decrease in GSH concentration due to conversion of GSH to GSNO and subsequently to GSSG. [ONOO−] does not follow a similar switch-like increase in its concentration. Solid curve is for [GSH]0 = 104 µM, dotted curve for [GSH]0 = 103 µM, and dashed curve with diamonds for [GSH]0 = 102 µM. The response is thus sharper and earlier in the presence of lower initial concentrations of GSH.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2386238&req=5

pone-0002249-g003: Time evolutions of A) GSH, B) N2O3, C) FeLnNO, and D) ONOO− predicted by Model II.N2O3 and FeLnNO increase to high concentrations by a switch-like mechanism induced by a decrease in GSH concentration due to conversion of GSH to GSNO and subsequently to GSSG. [ONOO−] does not follow a similar switch-like increase in its concentration. Solid curve is for [GSH]0 = 104 µM, dotted curve for [GSH]0 = 103 µM, and dashed curve with diamonds for [GSH]0 = 102 µM. The response is thus sharper and earlier in the presence of lower initial concentrations of GSH.
Mentions: The results from our calculations using Model II are shown in Figure 3. Here, we focused on the time evolution of four compounds, GSH, N2O3, FeLnNO and ONOO−, displayed in respective panels A–D. The NO species N2O3, FeLnNO and ONOO− have been proposed to carry out various indirect effects of NO on cellular pathways, including apoptosis, during inflammation [20].

Bottom Line: We propose a new mathematical model for simulating the effects of nitric oxide (NO) on apoptosis.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Biology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus