Computational Insights on the Competing Effects of Nitric Oxide in Regulating Apoptosis

Elife Z Bagci,Ivet Bahar,Yoram Vodovotz,Timothy R Billiar,Bard Ermentrout,Kathrin Maedler

doi:10.1371/journal.pone.0002249

Elife Z Bagci, Ivet Bahar + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0002249

Copy DOI

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 N2O3, non-heme iron nitrosyl species (FeLnNO), 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.

Highlights

The survival of an organism depends on homeostatic mechanisms that establish a balance between cell proliferation and cell death
The threshold [casp8]0 value for casp3 activation was 8.3561025 mM in Figure 2, where nitric oxide (NO) was not produced at all. This value remains the same for both [GSH]0 = 104 mM and 103 mM in the presence of NO, but increases to 9.9 61025 mM when [GSH]0 is 102 mM and to 1.26 61024 mM when [GSH]0 is zero, the different behavior observed in panel H. These results suggest that N2O3 does not affect the bistable character of the response to EC stimuli, except for modifying the threshold for onset of apoptosis, which is shifted to higher [casp8]0 with decreasing [GSH]0
We present here the results from simulations that incorporate the main chemical interactions of NO with components of the apoptotic interactions network, with the goal of shedding light on the dichotomous effects of NO on apoptosis

Summary

Introduction

The survival of an organism depends on homeostatic mechanisms that establish a balance between cell proliferation and cell death. A form of programmed cell death, assists in regulating cell proliferation. This process stands in contrast to necrosis, which is thought to be uncontrolled. Apoptosis may be induced by various events, such as binding of extracellular (EC) death signaling ligands to host cell receptors, the lack of pro-survival signals, and genetic damage. These events are usually followed by the activation of caspases, cysteine-dependent aspartate-specific proteases, which initiate and execute apoptosis. Caspases are activated through two major pathways: (a) liganddependent or receptor-induced activation (extrinsic pathway), involving death receptors such as Fas or the members of tumor necrosis factor (TNF) receptor superfamily, and (b) mitochondriadependent activation (intrinsic pathway) via cytochrome c (cyt c) release from mitochondria, triggered by stress, irradiation or inflammation [3,4]

Methods

Results

Conclusion