Location: Bagci 2008 @ 219d126f6f27 / bagci_2008a.cellml

Author:
Mathieu Deneux <mathieu.deneux@gmail.com>
Date:
2016-07-29 12:23:22+12:00
Desc:
Added a SEDML file
Permanent Source URI:
https://models.cellml.org/workspace/363/rawfile/219d126f6f274713b167ca4205b64eca68118808/bagci_2008a.cellml

<?xml version="1.0"?>
<!-- 
This CellML file was generated on 21/08/2009 at 9:19:39 at a.m. using:

COR (0.9.31.1309)
Copyright 2002-2009 Dr Alan Garny
http://cor.physiol.ox.ac.uk/ - cor@physiol.ox.ac.uk

CellML 1.0 was used to generate this model
http://www.cellml.org/
  --><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" cmeta:id="bagci_2008a" name="bagci_2008a">
 <documentation xmlns="http://cellml.org/tmp-documentation">
 <article>
 <section id="sec_status">
  <title>Model Status</title> 
  <para>This CellML model describes Model II (NO related reactions) in the published paper, and is able to reproduce figure 3 from the publication. The units have been checked and are consistent.</para> 
  </section>
 <sect1 id="sec_structure">
  <title>Model Structure</title> 
  <para>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.</para>
 
  <para>The original paper is cited below:</para> 
 <para>
  Computational Insights on the Competing Effects of Nitric Oxide in Regulating Apoptosis. Elift. Z. Bagci, Yoram Vodovotz et al, 2009, PLoS ONE, 3(5),e2249. 
  <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&amp;cmd=Retrieve&amp;dopt=AbstractPlus&amp;list_uids=18509469&amp;query_hl=1&amp;itool=pubmed_docsum">PubMed ID: 18509469</ulink>
  </para>
 
 <informalfigure float="0" id="fig_reaction_diagram">
 <mediaobject>
 <imageobject>
 <objectinfo>
  <title>Diagram of model</title> 
  </objectinfo>
  <imagedata fileref="bagci_2008a.png"/> 
  </imageobject>
  </mediaobject>
  <caption>A schematic diagram of biochemical pathways of NO related reactions.</caption> 
  </informalfigure>
  </sect1>
  </article>
  </documentation>   
   
   <units name="micromolar">
      <unit prefix="micro" units="mole"/>
      <unit exponent="-1" units="litre"/>
   </units>
   <units name="first_order_rate_constant">
      <unit exponent="-1" units="second"/>
   </units>
   <units name="second_order_rate_constant">
      <unit exponent="-1" units="second"/>
      <unit exponent="-1" units="micromolar"/>
   </units>
   <units name="flux">
      <unit units="micromolar"/>
      <unit exponent="-1" units="second"/>
   </units>
   <units name="rate2">
      <unit exponent="-2" units="micromolar"/>
      <unit exponent="-1" units="second"/>
   </units>
   <component name="environment">
      <variable cmeta:id="environment_time" name="time" public_interface="out" units="second"/>
   </component>
   <component name="NO">
      <variable cmeta:id="NO_NO" initial_value="0" name="NO" public_interface="out" units="micromolar"/>
      <variable name="O_2m" public_interface="in" units="micromolar"/>
      <variable cmeta:id="NO_O_2" initial_value="35" name="O_2" units="micromolar"/>
      <variable cmeta:id="NO_NO_2" initial_value="0" name="NO_2" units="micromolar"/>
      <variable name="N2O3" public_interface="in" units="micromolar"/>
      <variable name="GSNO" public_interface="in" units="micromolar"/>
      <variable cmeta:id="NO_CcOX" initial_value="0.1" name="CcOX" public_interface="out" units="micromolar"/>
      <variable name="FeLn" public_interface="in" units="micromolar"/>
      <variable name="r_1NO" units="flux"/>
      <variable name="r_4NO" public_interface="out" units="flux"/>
      <variable name="r_12aNO" units="flux"/>
      <variable name="r_12bNOp" public_interface="out" units="flux"/>
      <variable name="r_12bNOm" public_interface="out" units="flux"/>
      <variable name="r_14NO" public_interface="out" units="flux"/>
      <variable name="r_15NO" public_interface="out" units="flux"/>
      <variable name="r_16NO" public_interface="out" units="flux"/>
      <variable name="k_1NO" public_interface="in" units="flux"/>
      <variable name="k_4NO" public_interface="in" units="second_order_rate_constant"/>
      <variable name="k_12aNO" public_interface="in" units="rate2"/>
      <variable name="k_12bNOp" public_interface="in" units="second_order_rate_constant"/>
      <variable name="k_12bNOm" public_interface="in" units="first_order_rate_constant"/>
      <variable name="k_14NO" public_interface="in" units="first_order_rate_constant"/>
      <variable name="k_15NO" public_interface="in" units="second_order_rate_constant"/>
      <variable name="k_16NO" public_interface="in" units="second_order_rate_constant"/>
      <variable name="time" public_interface="in" units="second"/>
      <math xmlns="http://www.w3.org/1998/Math/MathML">
         <apply>
            <eq/>
            <ci>r_1NO</ci>
            <ci>k_1NO</ci>
         </apply>
         <apply>
            <eq/>
            <ci>r_4NO</ci>
            <apply>
               <times/>
               <ci>k_4NO</ci>
               <ci>NO</ci>
               <ci>O_2m</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_12aNO</ci>
            <apply>
               <times/>
               <ci>k_12aNO</ci>
               <apply>
                  <power/>
                  <ci>NO</ci>
                  <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
               </apply>
               <ci>O_2</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_12bNOp</ci>
            <apply>
               <times/>
               <ci>k_12bNOp</ci>
               <ci>NO_2</ci>
               <ci>NO</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_12bNOm</ci>
            <apply>
               <times/>
               <ci>k_12bNOm</ci>
               <ci>N2O3</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_14NO</ci>
            <apply>
               <times/>
               <ci>k_14NO</ci>
               <ci>GSNO</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_15NO</ci>
            <apply>
               <times/>
               <ci>k_15NO</ci>
               <ci>CcOX</ci>
               <ci>NO</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_16NO</ci>
            <apply>
               <times/>
               <ci>k_16NO</ci>
               <ci>FeLn</ci>
               <ci>NO</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>NO</ci>
            </apply>
            <apply>
               <minus/>
               <apply>
                  <minus/>
                  <apply>
                     <plus/>
                     <apply>
                        <minus/>
                        <apply>
                           <minus/>
                           <apply>
                              <minus/>
                              <ci>r_1NO</ci>
                              <ci>r_4NO</ci>
                           </apply>
                           <apply>
                              <times/>
                              <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
                              <ci>r_12aNO</ci>
                           </apply>
                        </apply>
                        <ci>r_12bNOp</ci>
                     </apply>
                     <ci>r_12bNOm</ci>
                     <ci>r_14NO</ci>
                  </apply>
                  <ci>r_15NO</ci>
               </apply>
               <ci>r_16NO</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>CcOX</ci>
            </apply>
            <apply>
               <minus/>
               <ci>r_15NO</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>NO_2</ci>
            </apply>
            <apply>
               <plus/>
               <apply>
                  <minus/>
                  <apply>
                     <times/>
                     <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
                     <ci>r_12aNO</ci>
                  </apply>
                  <ci>r_12bNOp</ci>
               </apply>
               <ci>r_12bNOm</ci>
            </apply>
         </apply>
      </math>
   </component>
   <component name="O_2m">
      <variable cmeta:id="O_2m_O_2m" initial_value="0" name="O_2m" public_interface="out" units="micromolar"/>
      <variable cmeta:id="O_2m_SOD" initial_value="10" name="SOD" public_interface="out" units="micromolar"/>
      <variable name="GSNO" public_interface="in" units="micromolar"/>
      <variable name="r_2NO" units="flux"/>
      <variable name="r_4NO" public_interface="in" units="flux"/>
      <variable name="r_5NO" public_interface="out" units="flux"/>
      <variable name="r_10NO" public_interface="out" units="flux"/>
      <variable name="k_2NO" public_interface="in" units="flux"/>
      <variable name="k_5NO" public_interface="in" units="second_order_rate_constant"/>
      <variable name="k_10NO" public_interface="in" units="rate2"/>
      <variable name="time" public_interface="in" units="second"/>
      <math xmlns="http://www.w3.org/1998/Math/MathML">
         <apply>
            <eq/>
            <ci>r_2NO</ci>
            <ci>k_2NO</ci>
         </apply>
         <apply>
            <eq/>
            <ci>r_5NO</ci>
            <apply>
               <times/>
               <ci>k_5NO</ci>
               <ci>SOD</ci>
               <ci>O_2m</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_10NO</ci>
            <apply>
               <times/>
               <ci>k_10NO</ci>
               <apply>
                  <power/>
                  <ci>GSNO</ci>
                  <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
               </apply>
               <ci>O_2m</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>O_2m</ci>
            </apply>
            <apply>
               <minus/>
               <apply>
                  <minus/>
                  <apply>
                     <minus/>
                     <ci>r_2NO</ci>
                     <ci>r_4NO</ci>
                  </apply>
                  <ci>r_5NO</ci>
               </apply>
               <ci>r_10NO</ci>
            </apply>
         </apply>
      </math>
   </component>
   <component name="ONOO_m">
      <variable cmeta:id="ONOO_m_ONOO_m" initial_value="0" name="ONOO_m" public_interface="out" units="micromolar"/>
      <variable name="GSH" public_interface="in" units="micromolar"/>
      <variable cmeta:id="ONOO_m_GPX" initial_value="5.8" name="GPX" units="micromolar"/>
      <variable cmeta:id="ONOO_m_CO_2" initial_value="1000" name="CO_2" units="micromolar"/>
      <variable cmeta:id="ONOO_m_Cyt_c" initial_value="400" name="Cyt_c" units="micromolar"/>
      <variable name="r_4NO" public_interface="in" units="flux"/>
      <variable name="r_6NO" public_interface="out" units="flux"/>
      <variable name="r_7NO" public_interface="out" units="flux"/>
      <variable name="r_8NO" public_interface="out" units="flux"/>
      <variable name="r_9NO" public_interface="out" units="flux"/>
      <variable name="k_6NO" public_interface="in" units="second_order_rate_constant"/>
      <variable name="k_7NO" public_interface="in" units="second_order_rate_constant"/>
      <variable name="k_8NO" public_interface="in" units="second_order_rate_constant"/>
      <variable name="k_9NO" public_interface="in" units="second_order_rate_constant"/>
      <variable name="time" public_interface="in" units="second"/>
      <math xmlns="http://www.w3.org/1998/Math/MathML">
         <apply>
            <eq/>
            <ci>r_6NO</ci>
            <apply>
               <times/>
               <ci>k_6NO</ci>
               <ci>ONOO_m</ci>
               <ci>GSH</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_7NO</ci>
            <apply>
               <times/>
               <ci>k_7NO</ci>
               <ci>ONOO_m</ci>
               <ci>GPX</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_8NO</ci>
            <apply>
               <times/>
               <ci>k_8NO</ci>
               <ci>ONOO_m</ci>
               <ci>CO_2</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_9NO</ci>
            <apply>
               <times/>
               <ci>k_9NO</ci>
               <ci>ONOO_m</ci>
               <ci>Cyt_c</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>ONOO_m</ci>
            </apply>
            <apply>
               <minus/>
               <apply>
                  <minus/>
                  <apply>
                     <minus/>
                     <apply>
                        <minus/>
                        <ci>r_4NO</ci>
                        <ci>r_6NO</ci>
                     </apply>
                     <ci>r_7NO</ci>
                  </apply>
                  <ci>r_8NO</ci>
               </apply>
               <ci>r_9NO</ci>
            </apply>
         </apply>
      </math>
   </component>
   <component name="GSH">
      <variable cmeta:id="GSH_GSH" initial_value="10000" name="GSH" public_interface="out" units="micromolar"/>
      <variable name="N2O3" public_interface="in" units="micromolar"/>
      <variable name="GSSG" units="micromolar"/>
      <variable name="FeLnNO" units="micromolar"/>
      <variable name="FeLn" public_interface="in" units="micromolar"/>
      <variable name="FeLn_0" public_interface="in" units="micromolar"/>
      <variable name="GSH_0" public_interface="in" units="micromolar"/>
      <variable name="GSNO" public_interface="in" units="micromolar"/>
      <variable name="r_6NO" public_interface="in" units="flux"/>
      <variable name="r_11NO" public_interface="out" units="flux"/>
      <variable name="r_m" units="flux"/>
      <variable name="r_17NO" public_interface="out" units="flux"/>
      <variable name="k_11NO" public_interface="in" units="second_order_rate_constant"/>
      <variable name="v_m" public_interface="in" units="flux"/>
      <variable name="k_m" public_interface="in" units="micromolar"/>
      <variable name="k_17NO" public_interface="in" units="second_order_rate_constant"/>
      <variable name="time" public_interface="in" units="second"/>
      <math xmlns="http://www.w3.org/1998/Math/MathML">
         <apply>
            <eq/>
            <ci>FeLnNO</ci>
            <apply>
               <minus/>
               <ci>FeLn_0</ci>
               <ci>FeLn</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>GSSG</ci>
            <apply>
               <divide/>
               <apply>
                  <minus/>
                  <apply>
                     <minus/>
                     <ci>GSH_0</ci>
                     <ci>GSH</ci>
                  </apply>
                  <ci>GSNO</ci>
               </apply>
               <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_11NO</ci>
            <apply>
               <times/>
               <ci>k_11NO</ci>
               <ci>N2O3</ci>
               <ci>GSH</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_m</ci>
            <apply>
               <divide/>
               <apply>
                  <times/>
                  <ci>v_m</ci>
                  <ci>GSSG</ci>
               </apply>
               <apply>
                  <plus/>
                  <ci>k_m</ci>
                  <ci>GSSG</ci>
               </apply>
            </apply>
         </apply>
         <apply>
            <eq/>
            <ci>r_17NO</ci>
            <apply>
               <times/>
               <ci>k_17NO</ci>
               <ci>FeLnNO</ci>
               <ci>GSH</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>GSH</ci>
            </apply>
            <apply>
               <minus/>
               <apply>
                  <plus/>
                  <apply>
                     <minus/>
                     <apply>
                        <minus/>
                        <ci>r_6NO</ci>
                     </apply>
                     <ci>r_11NO</ci>
                  </apply>
                  <apply>
                     <times/>
                     <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
                     <ci>r_m</ci>
                  </apply>
               </apply>
               <ci>r_17NO</ci>
            </apply>
         </apply>
      </math>
   </component>
   <component name="GSNO">
      <variable cmeta:id="GSNO_GSNO" initial_value="0" name="GSNO" public_interface="out" units="micromolar"/>
      <variable name="r_6NO" public_interface="in" units="flux"/>
      <variable name="r_10NO" public_interface="in" units="flux"/>
      <variable name="r_11NO" public_interface="in" units="flux"/>
      <variable name="r_14NO" public_interface="in" units="flux"/>
      <variable name="r_17NO" public_interface="in" units="flux"/>
      <variable name="time" public_interface="in" units="second"/>
      <math xmlns="http://www.w3.org/1998/Math/MathML">
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>GSNO</ci>
            </apply>
            <apply>
               <plus/>
               <apply>
                  <minus/>
                  <apply>
                     <plus/>
                     <apply>
                        <minus/>
                        <ci>r_6NO</ci>
                        <apply>
                           <times/>
                           <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
                           <ci>r_10NO</ci>
                        </apply>
                     </apply>
                     <ci>r_11NO</ci>
                  </apply>
                  <ci>r_14NO</ci>
               </apply>
               <ci>r_17NO</ci>
            </apply>
         </apply>
      </math>
   </component>
   <component name="N2O3">
      <variable cmeta:id="N2O3_N2O3" initial_value="0" name="N2O3" public_interface="out" units="micromolar"/>
      <variable name="r_11NO" public_interface="in" units="flux"/>
      <variable name="r_12bNOp" public_interface="in" units="flux"/>
      <variable name="r_12bNOm" public_interface="in" units="flux"/>
      <variable name="r_13NO" units="flux"/>
      <variable name="k_13NO" public_interface="in" units="first_order_rate_constant"/>
      <variable name="time" public_interface="in" units="second"/>
      <math xmlns="http://www.w3.org/1998/Math/MathML">
         <apply>
            <eq/>
            <ci>r_13NO</ci>
            <apply>
               <times/>
               <ci>k_13NO</ci>
               <ci>N2O3</ci>
            </apply>
         </apply>
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>N2O3</ci>
            </apply>
            <apply>
               <minus/>
               <apply>
                  <minus/>
                  <apply>
                     <plus/>
                     <apply>
                        <minus/>
                        <ci>r_11NO</ci>
                     </apply>
                     <ci>r_12bNOp</ci>
                  </apply>
                  <ci>r_12bNOm</ci>
               </apply>
               <ci>r_13NO</ci>
            </apply>
         </apply>
      </math>
   </component>
   <component name="FeLn">
      <variable cmeta:id="FeLn_FeLn" initial_value="0.05" name="FeLn" public_interface="out" units="micromolar"/>
      <variable name="r_16NO" public_interface="in" units="flux"/>
      <variable name="r_17NO" public_interface="in" units="flux"/>
      <variable name="time" public_interface="in" units="second"/>
      <math xmlns="http://www.w3.org/1998/Math/MathML">
         <apply>
            <eq/>
            <apply>
               <diff/>
               <bvar>
                  <ci>time</ci>
               </bvar>
               <ci>FeLn</ci>
            </apply>
            <apply>
               <plus/>
               <apply>
                  <minus/>
                  <ci>r_16NO</ci>
               </apply>
               <ci>r_17NO</ci>
            </apply>
         </apply>
      </math>
   </component>
   <component name="model_constant">
      <variable initial_value="1" name="k_1NO" public_interface="out" units="flux"/>
      <variable initial_value="0.1" name="k_2NO" public_interface="out" units="flux"/>
      <variable initial_value="6700" name="k_4NO" public_interface="out" units="second_order_rate_constant"/>
      <variable initial_value="2400" name="k_5NO" public_interface="out" units="second_order_rate_constant"/>
      <variable initial_value="0.00135" name="k_6NO" public_interface="out" units="second_order_rate_constant"/>
      <variable initial_value="2" name="k_7NO" public_interface="out" units="second_order_rate_constant"/>
      <variable initial_value="0.058" name="k_8NO" public_interface="out" units="second_order_rate_constant"/>
      <variable initial_value="0.025" name="k_9NO" public_interface="out" units="second_order_rate_constant"/>
      <variable initial_value="0.0006" name="k_10NO" public_interface="out" units="rate2"/>
      <variable initial_value="66" name="k_11NO" public_interface="out" units="second_order_rate_constant"/>
      <variable initial_value="0.000006" name="k_12aNO" public_interface="out" units="rate2"/>
      <variable initial_value="81000" name="k_12bNOm" public_interface="out" units="first_order_rate_constant"/>
      <variable initial_value="1100" name="k_12bNOp" public_interface="out" units="second_order_rate_constant"/>
      <variable initial_value="1600" name="k_13NO" public_interface="out" units="first_order_rate_constant"/>
      <variable initial_value="320" name="v_m" public_interface="out" units="flux"/>
      <variable initial_value="50" name="k_m" public_interface="out" units="micromolar"/>
      <variable initial_value="0.0002" name="k_14NO" public_interface="out" units="first_order_rate_constant"/>
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