Kinetic Modeling of Nitric-Oxide-Associated Reaction Network

Hu, Teh Min; Hayton, William L.; Mallery, Susan R.

doi:10.1007/s11095-006-9031-4

Cited by 21 publications

(24 citation statements)

References 48 publications

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“…The reaction of peroxynitrite with glutathione (GSH) (present at mM levels) was neglected because of a two order magnitude slower reaction rate constant (k=6.6×10 2 M −1 .s −1 ) difference as compared to reaction rate constant with CO 2 (k=1–2×10 4 M −1 .s −1 ) [17, 81]. However, NO (indirectly through its oxidation product N 2 O 3 ) and peroxynitrite (directly or through products of peroxynitrite decomposition and its reaction with CO 2 ) can nitrosate glutathione to form S- nitrosoglutathione (GSNO) [81–83], which is involved in a number of physiological processes including apoptosis, and response to oxidative and nitrosative stress [84, 85]. Overall, our results are in agreement with other studies that reported the lack of a plateau in peroxynitrite concentration [17].…”

Section: Discussionmentioning

confidence: 99%

Endothelial NO and O2− production rates differentially regulate oxidative, nitroxidative, and nitrosative stress in the microcirculation

Kar

Kavdia

2013

Free Radical Biology and Medicine

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Endothelial dysfunction causes an imbalance in endothelial NO and O2•− production rates and increased peroxynitrite formation. Peroxynitrite and its decomposition products cause multiple deleterious effects including tyrosine nitration of proteins, superoxide dismutase (SOD) inactivation and tissue damage. Studies have shown that peroxynitrite formation during endothelial dysfunction is strongly dependent on the NO and O2•− production rates. Previous experimental and modeling studies examining the role of NO and O2•− production imbalance on peroxynitrite formation showed different results in biological and synthetic systems. However, there is a lack of quantitative information about the formation and biological relevance of peroxynitrite in oxidative, nitroxidative and nitrosative stress conditions in the microcirculation. We developed a computational biotransport model to examine the role of endothelium NO and O2•− production on the complex biochemical NO and O2•− interactions in the microcirculation. We also modeled the effect of variability in SOD expression and activity during oxidative stress. The results showed that peroxynitrite concentration increased with increase in either O2•− to NO or NO to O2•− production rate ratios (QO2•−/QNO or QNO/QO2•−, respectively). The peroxynitrite concentrations were similar for both production rate ratios indicating that peroxynitrite related nitroxidative and nitrosative stresses may be similar in endothelial dysfunction or iNOS induced NO production. The endothelial peroxynitrite concentration increased with increase in both QO2•−/QNO or QNO/QO2•− ratios at SOD concentrations 0.1–100 μM. The absence of SOD may not mitigate the extent of peroxynitrite mediated toxicity as we predicted insignificant increase in peroxynitrite levels beyond QO2•−/QNO and QNO/QO2•−ratio of 1. The results support the experimental observations of biological systems and show that peroxynitrite formation increases with increase in either NO or O2•− production and excess NO production from iNOS or from NO donors during oxidative stress conditions does not reduce the extent of peroxynitrite mediated toxicity.

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Section: Discussionmentioning

confidence: 99%

Endothelial NO and O2− production rates differentially regulate oxidative, nitroxidative, and nitrosative stress in the microcirculation

Kar

Kavdia

2013

Free Radical Biology and Medicine

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“…Following this, the remaining differential equations are added one by one, and bistability is checked each time a new reaction is added to finally obtain the whole set of equations in the apoptotic pathway. The rate constants of these reactions are taken from the literature (Bagci et al 2008) and (Hu et al 2006). This procedure is used for both models 1 and 2.…”

Section: Methodsmentioning

confidence: 99%

“…In their mathematical model, NO-related reactions were integrated into the mitochondriadependent apoptosis model (Bagci et al 2006). The kinetic parameters of the simulations were selected from a wide parameter range in the literature (Hu et al 2006). Computations on this model aimed to understand the regulatory effect of the reactive NO species namely N 2 O 3 , non-heme iron nitrosyl species (FeL n NO), and peroxynitrite (ONOO − ).…”

Section: Introductionmentioning

confidence: 99%

Bistability Analysis of an Apoptosis Model in the Presence of Nitric Oxide

2010

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Bistability in apoptosis, or programmed cell death, is crucial for the healthy functioning of multicellular organisms. The aim in this study is to show the presence of bistability in a mitochondria-dependent apoptosis model under nitric oxide effects using chemical reaction network theory. The model equations are a set of coupled ordinary differential equations arising from the assumed mass action kinetics. Whether these equations have a capacity for bistability (cell survival and apoptosis) is determined using a modular approach in which the model is decomposed into modules. Each module contains only a subset of the whole model and is analyzed separately. It is seen that bistability in a module is preserved throughout the whole model after adding the remaining reactions in the pathway on these modules. It is also found that inhibitor effect of some proteins and the appearance of a reacting protein in a later stage as a product is a desired feature but not sufficient for bistability (in the absence of cooperativity effects). On the whole model, two apoptotic and two cell survival states are obtained depending on the initial cell conditions. The results suggest that the antiapoptotic effects of nitric oxide species are responsible for the bistable character of the apoptotic pathway when cooperativity is not assumed in the apoptosome formation.

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“…The kinetic models of NO, O 2 - , and ONOO − studied diverse aspects of roles of these molecules, which included (1) the kinetics of reaction of NO and superoxide, 46-48 (2) superoxide dismutation catalyzed by superoxide dismutase, 44,45,49,50 (3) role of GSH, 46 and (4) models of O 2 - production from mitochondrial transport chain.…”

Section: Kinetic Modelsmentioning

confidence: 99%

Mathematical and Computational Models of Oxidative and Nitrosative Stress

Kavdia

2011

Crit Rev Biomed Eng

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The importance of nitric oxide (NO), superoxide (O2−), and peroxynitrite (ONOO−) interactions in physiologic functions and pathophysiological conditions such as cardiovascular disease, hypertension, and diabetes have been established extensively in in vivo and in vitro studies. Despite intense investigation of NO, O2−, and ONOO− biochemical interactions, fundamental questions regarding the role of these molecules remain unanswered. Mathematical models based on fundamental principles of mass balance and reaction kinetics have provided significant results in the case of NO. However, the models that include interaction of NO, O2−, and ONOO− have been few because of the complexity of these interactions. Not only do these mathematical and computational models provided quantitative knowledge of distributions and concentrations of NO, O2−, and ONOO− under normal physiologic and pathophysiologic conditions, they also can help to answer specific hypotheses. The focus of this review article is on the models that involve more than one of the 3 molecules (NO, O2−, and ONOO−). Specifically, kinetic models of O2− dismutase and tyrosine nitration and biotransport models in the microcirculation are reviewed. In addition, integrated experimental and computational models of dynamics of NO/O2−/ONOO− in diverse systems are reviewed.

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Kinetic Modeling of Nitric-Oxide-Associated Reaction Network

Abstract: The model predicts that concurrent high nitric oxide and superoxide generation--such as in the inflammatory conditions--may result in nonlinear system dynamics, and glutathione may serve as a dynamic switch of N203 mediated nitrosation reaction.

Cited by 21 publications

References 48 publications

Endothelial NO and O2− production rates differentially regulate oxidative, nitroxidative, and nitrosative stress in the microcirculation

Endothelial NO and O2− production rates differentially regulate oxidative, nitroxidative, and nitrosative stress in the microcirculation

Bistability Analysis of an Apoptosis Model in the Presence of Nitric Oxide

Mathematical and Computational Models of Oxidative and Nitrosative Stress

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