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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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(A) Mitochondria-dependent apoptotic pathways in Model I.The dotted box includes the interactions considered in the model. Solid arrows indicate chemical reactions or upregulation; those terminated by a bar indicate inhibition or downregulation; and dashed arrows indicate subcellular translocation. The components of the model are procaspase-8 (pro8), procaspase-3 (pro3), procaspase-9 (pro9), caspase-8 (casp8), caspase-9 (casp9), caspase-3 (casp3), IAP (inhibitor of apoptosis), cytochrome c (cyt c), Apaf-1, the heptameric apoptosome complex (apop), the mitochondrial permeability transition pore complex (PTPC), p53, Bcl-2, Bax, Bid, truncated Bid (tBid). The reader is referred to our previous work [28] for more details. Three compounds (N2O3, FeLnNO and ONOO−) not included in the original Model I [28] are highlighted. These compounds establish the connection with the nitric oxide pathways delineated in panel B. (B) Nitric oxide (NO)-related reactions in Model II. The following compounds are included: ONOO− (peroxynitrite), GPX (glutathione peroxidase), O2− (superoxide), GSH (glutathione), GSNO (nitrosoglutathione), GSSG (glutathione disulfide), CcOX (cytochrome c oxidase), SOD (superoxide dismutase), FeLn (non-heme iron compounds), FeLnNO (non-heme iron nitrosyl compounds), NADPH (reduced form of nicotinamide adenine dinucleotide phosphate), NADP+ (oxidized form of nicotinamide adenine dinucleotide phosphate). FeLnNO, ONOO− and N2O3, highlighted in both panels A and B, bridge between Models I to II. Model III integrates both sets of reactions/pathways through these compounds. GSH modulates their concentrations by reacting with them. GSH is converted by these reactions to GSNO, which is then converted to GSSG and finally back to GSH. Those compounds and interactions are shown in blue. See Table 1 for the complete list of reactions and rate constants.
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pone-0002249-g001: (A) Mitochondria-dependent apoptotic pathways in Model I.The dotted box includes the interactions considered in the model. Solid arrows indicate chemical reactions or upregulation; those terminated by a bar indicate inhibition or downregulation; and dashed arrows indicate subcellular translocation. The components of the model are procaspase-8 (pro8), procaspase-3 (pro3), procaspase-9 (pro9), caspase-8 (casp8), caspase-9 (casp9), caspase-3 (casp3), IAP (inhibitor of apoptosis), cytochrome c (cyt c), Apaf-1, the heptameric apoptosome complex (apop), the mitochondrial permeability transition pore complex (PTPC), p53, Bcl-2, Bax, Bid, truncated Bid (tBid). The reader is referred to our previous work [28] for more details. Three compounds (N2O3, FeLnNO and ONOO−) not included in the original Model I [28] are highlighted. These compounds establish the connection with the nitric oxide pathways delineated in panel B. (B) Nitric oxide (NO)-related reactions in Model II. The following compounds are included: ONOO− (peroxynitrite), GPX (glutathione peroxidase), O2− (superoxide), GSH (glutathione), GSNO (nitrosoglutathione), GSSG (glutathione disulfide), CcOX (cytochrome c oxidase), SOD (superoxide dismutase), FeLn (non-heme iron compounds), FeLnNO (non-heme iron nitrosyl compounds), NADPH (reduced form of nicotinamide adenine dinucleotide phosphate), NADP+ (oxidized form of nicotinamide adenine dinucleotide phosphate). FeLnNO, ONOO− and N2O3, highlighted in both panels A and B, bridge between Models I to II. Model III integrates both sets of reactions/pathways through these compounds. GSH modulates their concentrations by reacting with them. GSH is converted by these reactions to GSNO, which is then converted to GSSG and finally back to GSH. Those compounds and interactions are shown in blue. See Table 1 for the complete list of reactions and rate constants.

Mentions: First, we illustrate how different strengths of EC pro-apoptotic signals may result in opposite qualitative responses or different quantitative (time-dependent) responses in the same type of cells [37], using our recently introduced bistable model [28] (illustrated in Figure 1A). Then, we examine the differences in the bistable response of diverse NO producing cells, e.g. cells with different concentrations of GSH and FeLn-and in different settings, i.e., with or without production of superoxide.


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)

(A) Mitochondria-dependent apoptotic pathways in Model I.The dotted box includes the interactions considered in the model. Solid arrows indicate chemical reactions or upregulation; those terminated by a bar indicate inhibition or downregulation; and dashed arrows indicate subcellular translocation. The components of the model are procaspase-8 (pro8), procaspase-3 (pro3), procaspase-9 (pro9), caspase-8 (casp8), caspase-9 (casp9), caspase-3 (casp3), IAP (inhibitor of apoptosis), cytochrome c (cyt c), Apaf-1, the heptameric apoptosome complex (apop), the mitochondrial permeability transition pore complex (PTPC), p53, Bcl-2, Bax, Bid, truncated Bid (tBid). The reader is referred to our previous work [28] for more details. Three compounds (N2O3, FeLnNO and ONOO−) not included in the original Model I [28] are highlighted. These compounds establish the connection with the nitric oxide pathways delineated in panel B. (B) Nitric oxide (NO)-related reactions in Model II. The following compounds are included: ONOO− (peroxynitrite), GPX (glutathione peroxidase), O2− (superoxide), GSH (glutathione), GSNO (nitrosoglutathione), GSSG (glutathione disulfide), CcOX (cytochrome c oxidase), SOD (superoxide dismutase), FeLn (non-heme iron compounds), FeLnNO (non-heme iron nitrosyl compounds), NADPH (reduced form of nicotinamide adenine dinucleotide phosphate), NADP+ (oxidized form of nicotinamide adenine dinucleotide phosphate). FeLnNO, ONOO− and N2O3, highlighted in both panels A and B, bridge between Models I to II. Model III integrates both sets of reactions/pathways through these compounds. GSH modulates their concentrations by reacting with them. GSH is converted by these reactions to GSNO, which is then converted to GSSG and finally back to GSH. Those compounds and interactions are shown in blue. See Table 1 for the complete list of reactions and rate constants.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002249-g001: (A) Mitochondria-dependent apoptotic pathways in Model I.The dotted box includes the interactions considered in the model. Solid arrows indicate chemical reactions or upregulation; those terminated by a bar indicate inhibition or downregulation; and dashed arrows indicate subcellular translocation. The components of the model are procaspase-8 (pro8), procaspase-3 (pro3), procaspase-9 (pro9), caspase-8 (casp8), caspase-9 (casp9), caspase-3 (casp3), IAP (inhibitor of apoptosis), cytochrome c (cyt c), Apaf-1, the heptameric apoptosome complex (apop), the mitochondrial permeability transition pore complex (PTPC), p53, Bcl-2, Bax, Bid, truncated Bid (tBid). The reader is referred to our previous work [28] for more details. Three compounds (N2O3, FeLnNO and ONOO−) not included in the original Model I [28] are highlighted. These compounds establish the connection with the nitric oxide pathways delineated in panel B. (B) Nitric oxide (NO)-related reactions in Model II. The following compounds are included: ONOO− (peroxynitrite), GPX (glutathione peroxidase), O2− (superoxide), GSH (glutathione), GSNO (nitrosoglutathione), GSSG (glutathione disulfide), CcOX (cytochrome c oxidase), SOD (superoxide dismutase), FeLn (non-heme iron compounds), FeLnNO (non-heme iron nitrosyl compounds), NADPH (reduced form of nicotinamide adenine dinucleotide phosphate), NADP+ (oxidized form of nicotinamide adenine dinucleotide phosphate). FeLnNO, ONOO− and N2O3, highlighted in both panels A and B, bridge between Models I to II. Model III integrates both sets of reactions/pathways through these compounds. GSH modulates their concentrations by reacting with them. GSH is converted by these reactions to GSNO, which is then converted to GSSG and finally back to GSH. Those compounds and interactions are shown in blue. See Table 1 for the complete list of reactions and rate constants.
Mentions: First, we illustrate how different strengths of EC pro-apoptotic signals may result in opposite qualitative responses or different quantitative (time-dependent) responses in the same type of cells [37], using our recently introduced bistable model [28] (illustrated in Figure 1A). Then, we examine the differences in the bistable response of diverse NO producing cells, e.g. cells with different concentrations of GSH and FeLn-and in different settings, i.e., with or without production of superoxide.

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