Koo2013 - Integrated shear stress induced NO production model

  public model
Model Identifier
BIOMD0000000468
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
Vijayalakshmi Chelliah, administrator

Metadata information

is
BioModels Database MODEL1308190000
BioModels Database BIOMD0000000468
isDerivedFrom
BioModels Database BIOMD0000000466
BioModels Database BIOMD0000000464
BioModels Database BIOMD0000000465
BioModels Database BIOMD0000000467
isDescribedBy
PubMed 23708369
hasTaxon
Taxonomy Homo sapiens

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000468_url.xml SBML L2V4 representation of Koo2013 - Integrated shear stress induced NO production model 418.71 KB Preview | Download

Additional files

BIOMD0000000468.pdf Auto-generated PDF file 563.28 KB Preview | Download
Integratedmodel_shearstress.cps Copasi file for the plot that corresponds to NO production under shear stress condition (red). 755.50 KB Preview | Download
BIOMD0000000468.m Auto-generated Octave file 30.31 KB Preview | Download
BIOMD0000000468.vcml Auto-generated VCML file 882.00 bytes Preview | Download
BIOMD0000000468.sci Auto-generated Scilab file 205.00 bytes Preview | Download
BIOMD0000000468_urn.xml Auto-generated SBML file with URNs 416.65 KB Preview | Download
BIOMD0000000468.svg Auto-generated Reaction graph (SVG) 252.53 KB Preview | Download
Integratedmodel_noshearstress.cps Copasi file for the plot that corresponds to NO production without shear stress condition (green). Without shear stress implies that the shear activating reactions (re5, re57, re102 and re103) are removed from the model. 725.58 KB Preview | Download
BIOMD0000000468-biopax3.owl Auto-generated BioPAX (Level 3) 176.30 KB Preview | Download
BIOMD0000000468-biopax2.owl Auto-generated BioPAX (Level 2) 106.99 KB Preview | Download
BIOMD0000000468.xpp Auto-generated XPP file 22.70 KB Preview | Download
BIOMD0000000468.png Auto-generated Reaction graph (PNG) 1.65 MB Preview | Download

  • Model originally submitted by : Vijayalakshmi Chelliah
  • Submitted: 19-Aug-2013 12:44:22
  • Last Modified: 21-Dec-2018 17:19:59
Revisions
  • Version: 3 public model Download this version
    • Submitted on: 21-Dec-2018 17:19:59
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: Integratedmodel_noshearstress.cps, Integratedmodel_shearstress.cps
  • Version: 2 public model Download this version
    • Submitted on: 22-May-2014 18:39:16
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Current version of Koo2013 - Integrated shear stress induced NO production model
  • Version: 1 public model Download this version
    • Submitted on: 19-Aug-2013 12:44:22
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Original import of Koo2013 - Integrated shear stress induced NO production model
Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
(L-Arg) => (NO)

([L-Arg]) => ([nitric oxide])
K_cam_no*(s45+s58)+K_p_no*(s62+s65)+K_pcam_no*s60

K_cam_no*([calcium(2+); Calmodulin-3Calmodulin-1Calmodulin-2]+[calcium(2+); Heat shock protein HSP 90-beta; Calmodulin-3Calmodulin-1Calmodulin-2])+K_p_no*([calcium(2+); Calmodulin-3Calmodulin-1Calmodulin-2; Heat shock protein HSP 90-beta; phosphorylated residue]+[Heat shock protein HSP 90-beta; phosphorylated residue])+K_pcam_no*[calcium(2+); Calmodulin-3Calmodulin-1Calmodulin-2; Heat shock protein HSP 90-beta; phosphorylated residue]
K_cam_no=17.0 inv_sec; K_p_no=5.0 inv_sec; K_pcam_no=17.0 inv_sec
(Hsp90-p-eNOS) => (Hsp90-eNOS)

([Heat shock protein HSP 90-beta; phosphorylated residue]) => ([Heat shock protein HSP 90-beta])
Vdp*s65/(s65+Kmdp)

Vdp*[Heat shock protein HSP 90-beta; phosphorylated residue]/([Heat shock protein HSP 90-beta; phosphorylated residue]+Kmdp)
Vdp = 4.0 sub_sec; Kmdp = 20.0 substance
(Hsp90-p-eNOS) => (s118 + Hsp90)

([Heat shock protein HSP 90-beta; phosphorylated residue]) => ([s118] + [Heat shock protein HSP 90-beta])
kDD*s65

kDD*[Heat shock protein HSP 90-beta; phosphorylated residue]
kDD = 9.45E-5 inv_sec
(Hsp90-eNOS) => (eNOS-Cav-1 + Hsp90)

([Heat shock protein HSP 90-beta]) => ([Caveolin-1] + [Heat shock protein HSP 90-beta])
kr90*s66

kr90*[Heat shock protein HSP 90-beta]
kr90 = 1.5 inv_sec
(Shc + p-FAK) => (p-FAK:Shc)

([SHC-transforming protein 1] + [Focal adhesion kinase 1; phosphorylated residue]) => ([Focal adhesion kinase 1; SHC-transforming protein 1; phosphorylated residue])
k105*s91*s93-k_105*s110

k105*[SHC-transforming protein 1]*[Focal adhesion kinase 1; phosphorylated residue]-k_105*[Focal adhesion kinase 1; SHC-transforming protein 1; phosphorylated residue]
k_105=1.0 inv_sec; k105=0.1 inv_nM_s
(Src) => (p-Src)

([Proto-oncogene tyrosine-protein kinase Src]) => ([Proto-oncogene tyrosine-protein kinase Src; phosphorylated residue])
exp(unity-(s39/tf)^1.3)*normal*(s39/unimol)^0.3*(unity-(s39/tf)^1.3)

exp(unity-([Time]/tf)^1.3)*normal*([Time]/unimol)^0.3*(unity-([Time]/tf)^1.3)
tf=540.0 substance; normal=0.026 nM_inv_s; unimol=1.0 substance; unity=1.0 dimensionless
(JNKK) => (p-JNKK)

([Dual specificity mitogen-activated protein kinase kinase 7]) => ([Dual specificity mitogen-activated protein kinase kinase 7; phosphorylated residue])
k19*s101*s96/(K19+s96)

k19*[Mitogen-activated protein kinase kinase kinase 1; phosphorylated residue]*[Dual specificity mitogen-activated protein kinase kinase 7]/(K19+[Dual specificity mitogen-activated protein kinase kinase 7])
k19=0.005 inv_sec; K19=15.0 substance
(MEKK1) => (p-MEKK1)

([Mitogen-activated protein kinase kinase kinase 1]) => ([Mitogen-activated protein kinase kinase kinase 1; phosphorylated residue])
k113*s102*s97/(K113+s97)

k113*[GTP(3-); GTPase HRas]*[Mitogen-activated protein kinase kinase kinase 1]/(K113+[Mitogen-activated protein kinase kinase kinase 1])
k113=0.035 inv_sec; K113=10.0 substance
(p-MEKK1) => (MEKK1)

([Mitogen-activated protein kinase kinase kinase 1; phosphorylated residue]) => ([Mitogen-activated protein kinase kinase kinase 1])
V18*s101/(K18+s101)

V18*[Mitogen-activated protein kinase kinase kinase 1; phosphorylated residue]/(K18+[Mitogen-activated protein kinase kinase kinase 1; phosphorylated residue])
V18=0.125 nM_inv_s; K18=8.0 substance
(p-Shc:Grb2:Sos) => (p-Shc + Grb2:Sos)

([SHC-transforming protein 1; Growth factor receptor-bound protein 2; Son of sevenless homolog 1; phosphorylated residue]) => ([SHC-transforming protein 1; phosphorylated residue] + [Son of sevenless homolog 1; Growth factor receptor-bound protein 2])
k9*s114

k9*[SHC-transforming protein 1; Growth factor receptor-bound protein 2; Son of sevenless homolog 1; phosphorylated residue]
k9=40.8 inv_sec
(p-JNK) => (JNK)

([Mitogen-activated protein kinase 8; phosphorylated residue]) => ([Mitogen-activated protein kinase 8])
V22*s104/(s104+K22)

V22*[Mitogen-activated protein kinase 8; phosphorylated residue]/([Mitogen-activated protein kinase 8; phosphorylated residue]+K22)
V22=0.05 nM_inv_s; K22=15.0 substance
(p-JNKK) => (JNKK)

([Dual specificity mitogen-activated protein kinase kinase 7; phosphorylated residue]) => ([Dual specificity mitogen-activated protein kinase kinase 7])
V20*s100/(s100+K20)

V20*[Dual specificity mitogen-activated protein kinase kinase 7; phosphorylated residue]/([Dual specificity mitogen-activated protein kinase kinase 7; phosphorylated residue]+K20)
V20=0.375 nM_inv_s; K20=15.0 substance
Curator's comment:
(added: 19 Aug 2013, 14:33:04, updated: 19 Aug 2013, 14:33:04)
The model is the integration of the all the sub-models (MODEL1302180003-6) described in the paper. Figure 6 of the paper is reproduced here. The model as such reproduces the plot that corresponds to NO production under shear-stress condition (red). To obtain the plot for NO production under no-shear-stress condition (green), shear activating reactions (re5, re57, re102 and re103) should be removed. The corresponding Copasi files can be downloaded below.