Koo2013 - Shear stress induced eNOS expression - Model 3

  public model
Model Identifier
BIOMD0000000466
Short description
Format
SBML (L2V4)
Related Publication
  • In silico modeling of shear-stress-induced nitric oxide production in endothelial cells through systems biology.
  • Koo A, Nordsletten D, Umeton R, Yankama B, Ayyadurai S, García-Cardeña G, Dewey CF Jr
  • Biophysical journal , 5/ 2013 , Volume 104 , pages: 2295-2306 , PubMed ID: 23708369
  • Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way.
Contributors
Andrew Koo

Metadata information

is
BioModels Database MODEL1302180005
BioModels Database BIOMD0000000466
isDescribedBy
PubMed 23708369
hasTaxon
Taxonomy Homo sapiens
isVersionOf
Gene Ontology nitric oxide biosynthetic process
Gene Ontology nitric oxide production involved in inflammatory response
Reactome eNOS synthesizes NO
Gene Ontology response to fluid shear stress
Curation status
Curated
Original model(s)
N/A
Tags
Name Description Size Actions

Model files
BIOMD0000000466_url.xml SBML L2V4 representation of Koo2013 - Shear stress induced eNOS expression - Model 3 191.85 KB Preview | Download

Additional files
BIOMD0000000466.xpp Auto-generated XPP file 9.68 KB Preview | Download
BIOMD0000000466.png Auto-generated Reaction graph (PNG) 421.44 KB Preview | Download
BIOMD0000000466.m Auto-generated Octave file 13.99 KB Preview | Download
BIOMD0000000466.sci Auto-generated Scilab file 205.00 bytes Preview | Download
BIOMD0000000466-biopax3.owl Auto-generated BioPAX (Level 3) 69.15 KB Preview | Download
BIOMD0000000466-biopax2.owl Auto-generated BioPAX (Level 2) 43.63 KB Preview | Download
BIOMD0000000466_urn.xml Auto-generated SBML file with URNs 190.76 KB Preview | Download
BIOMD0000000466.pdf Auto-generated PDF file 303.27 KB Preview | Download
BIOMD0000000466.svg Auto-generated Reaction graph (SVG) 95.75 KB Preview | Download
BIOMD0000000466.vcml Auto-generated VCML file 86.74 KB Preview | Download

  • Model originally submitted by : Andrew Koo
  • Submitted: 18-Feb-2013 20:27:51
  • Last Modified: 07-Apr-2014 04:00:36
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 07-Apr-2014 04:00:36
    • Submitted by: Andrew Koo
    • With comment: Current version of Koo2013 - Shear stress induced eNOS expression - Model 3
  • Version: 1 public model Download this version
    • Submitted on: 18-Feb-2013 20:27:51
    • Submitted by: Andrew Koo
    • With comment: Original import of BIOMD0000000466.xml.origin
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
p-JNKK

Dual specificity mitogen-activated protein kinase kinase 7 ; phosphorylated residue 		0.288 1E-9*mol
p-MEKK1

Mitogen-activated protein kinase kinase kinase 1 ; phosphorylated residue 		1.486 1E-9*mol
Ras:GTP

GTP(3-) ; GTPase HRas 		0.616 1E-9*mol
p-JNK

Mitogen-activated protein kinase 8 ; phosphorylated residue 		0.003 1E-9*mol
KLF2

Krueppel-like factor 2 		0.0 1E-9*mol
aAP-1

protein modification 		0.0 1E-9*mol
p-FAK:Shc

Focal adhesion kinase 1 ; SHC-transforming protein 1 ; phosphorylated residue 		0.857 1E-9*mol
Grb2:Sos

Son of sevenless homolog 1 ; Growth factor receptor-bound protein 2 		3.23 1E-9*mol
p-FAK:p-Shc:Grb2:Sos

Focal adhesion kinase 1 ; SHC-transforming protein 1 ; Son of sevenless homolog 1 ; Growth factor receptor-bound protein 2 ; phosphorylated residue 		5.577 1E-9*mol
Ras:GDP

GDP ; GTPase HRas 		119.384 1E-9*mol
Reactions
Reactions Rate Parameters
(p-JNKK) => (pp-JNKK)

([Dual specificity mitogen-activated protein kinase kinase 7; phosphorylated residue]) => ([Dual specificity mitogen-activated protein kinase kinase 7; phosphorylated residue])		 k15*s100*s101/(Km15+s100)

k15*[Dual specificity mitogen-activated protein kinase kinase 7; phosphorylated residue]*[Mitogen-activated protein kinase kinase kinase 1; phosphorylated residue]/(Km15+[Dual specificity mitogen-activated protein kinase kinase 7; phosphorylated residue])		 Km15=15.0 substance; k15=0.005 inv_sec
(MEKK1) => (p-MEKK1)

([Mitogen-activated protein kinase kinase kinase 1]) => ([Mitogen-activated protein kinase kinase kinase 1; phosphorylated residue])		 k11*s102*s97/(Km11+s97)

k11*[GTP(3-); GTPase HRas]*[Mitogen-activated protein kinase kinase kinase 1]/(Km11+[Mitogen-activated protein kinase kinase kinase 1])		 k11=0.035 inv_sec; Km11=10.0 substance
(Ras:GTP) => (Ras:GDP)

([GTP(3-); GTPase HRas]) => ([GDP; GTPase HRas])		 V10*s102/(Km10+s102)

V10*[GTP(3-); GTPase HRas]/(Km10+[GTP(3-); GTPase HRas])		 Km10=0.0571 substance; V10=0.289 nM_inv_s
(JNK) => (p-JNK)

([Mitogen-activated protein kinase 8]) => ([Mitogen-activated protein kinase 8; phosphorylated residue])		 k17*s99*s43/(s99+Km17)

k17*[Mitogen-activated protein kinase 8]*[Dual specificity mitogen-activated protein kinase kinase 7; phosphorylated residue]/([Mitogen-activated protein kinase 8]+Km17)		 k17=0.002 inv_sec; Km17=30.0 substance
(pp-JNK) => (p-JNK)

([Mitogen-activated protein kinase 8; phosphorylated residue]) => ([Mitogen-activated protein kinase 8; phosphorylated residue])		 V20*s44/(Km20+s44)

V20*[Mitogen-activated protein kinase 8; phosphorylated residue]/(Km20+[Mitogen-activated protein kinase 8; phosphorylated residue])		 V20=0.05 nM_inv_s; Km20=15.0 substance
(KLF2) => (KLF2)

([Krueppel-like factor 2]) => ([Krueppel-like factor 2])		 exp(tau*(delay-s39/tc))/(1+2*exp(tau*(delay-s39/tc))+exp(2*tau*(delay-s39/tc)))/uc*29.256

exp(tau*(delay-[Time]/tc))/(1+2*exp(tau*(delay-[Time]/tc))+exp(2*tau*(delay-[Time]/tc)))/uc*29.256		 uc=3600.0 dimensionless; tau=0.55 dimensionless; unity=20.0 nM_inv_s; tc=3600.0 substance; delay=5.0 dimensionless
(AP-1) => (aAP-1)

([AP-1]) => ([protein modification])		 s44*s42*k21/(Km21+s42)

[Mitogen-activated protein kinase 8; phosphorylated residue]*[AP-1]*k21/(Km21+[AP-1])		 k21=4.0E-5 inv_sec; Km21=25.0 substance
(p-FAK:Shc) => (p-FAK:p-Shc)

([Focal adhesion kinase 1; SHC-transforming protein 1; phosphorylated residue]) => ([Focal adhesion kinase 1; SHC-transforming protein 1; phosphorylated residue])		 k4*s110*s92-kr4*s112

k4*[Focal adhesion kinase 1; SHC-transforming protein 1; phosphorylated residue]*[Proto-oncogene tyrosine-protein kinase Src; phosphorylated residue]-kr4*[Focal adhesion kinase 1; SHC-transforming protein 1; phosphorylated residue]		 kr4=5.0 inv_sec; k4=8.33 inv_nM_s
(p-FAK:p-Shc + Grb2:Sos) => (p-FAK:p-Shc:Grb2:Sos)

([Focal adhesion kinase 1; SHC-transforming protein 1; phosphorylated residue] + [Son of sevenless homolog 1; Growth factor receptor-bound protein 2]) => ([Focal adhesion kinase 1; SHC-transforming protein 1; Son of sevenless homolog 1; Growth factor receptor-bound protein 2; phosphorylated residue])		 k5*s111*s112-kr5*s113

k5*[Son of sevenless homolog 1; Growth factor receptor-bound protein 2]*[Focal adhesion kinase 1; SHC-transforming protein 1; phosphorylated residue]-kr5*[Focal adhesion kinase 1; SHC-transforming protein 1; Son of sevenless homolog 1; Growth factor receptor-bound protein 2; phosphorylated residue]		 kr5=546.0 inv_sec; k5=60.0 inv_nM_s
(p-Shc:Grb2:Sos) => (p-Shc + Grb2:Sos)

([Son of sevenless homolog 1; Growth factor receptor-bound protein 2; SHC-transforming protein 1; phosphorylated residue]) => ([SHC-transforming protein 1; phosphorylated residue] + [Son of sevenless homolog 1; Growth factor receptor-bound protein 2])		 k7*s114

k7*[Son of sevenless homolog 1; Growth factor receptor-bound protein 2; SHC-transforming protein 1; phosphorylated residue]		 k7=40.8 inv_sec
(p-MEKK1) => (MEKK1)

([Mitogen-activated protein kinase kinase kinase 1; phosphorylated residue]) => ([Mitogen-activated protein kinase kinase kinase 1])		 V12*s101/(Km12+s101)

V12*[Mitogen-activated protein kinase kinase kinase 1; phosphorylated residue]/(Km12+[Mitogen-activated protein kinase kinase kinase 1; phosphorylated residue])		 V12=0.125 nM_inv_s; Km12=8.0 substance
(Ras:GDP) => (Ras:GTP)

([GDP; GTPase HRas]) => ([GTP(3-); GTPase HRas])		 k9*s114*s103/(s103+Km9)

k9*[Son of sevenless homolog 1; Growth factor receptor-bound protein 2; SHC-transforming protein 1; phosphorylated residue]*[GDP; GTPase HRas]/([GDP; GTPase HRas]+Km9)		 Km9=0.181 substance; k9=0.222 inv_sec
Curator's comment:
(added: 19 Aug 2013, 13:57:38, updated: 19 Aug 2013, 13:57:38)
The paper describes four sub-models and an integrated version of the four sub-models. This model corresponds to Model 3 - Shear stress induced eNOS expression. Figure 3C of the paper is reproduced here using Copasi 4.10 (Build 55).