Vascular and perivascular nitric oxide release and transport: biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3)
Catherine
Lloyd
Bioengineering Institute, University of Auckland
Model Status
This model is known to run in PCEnv and COR and is known to be mathematically consistent with the publication it was based on. This model has had an equation added to allow it to reproduce Figure 2 of the publication. The three different graphs of this figure can be produced by altering the variable 'Fe3' in the 'Fe3' component (this variable represents the concentration of NOS-1 in its Fe3+ bound state) to 0.6 or 0.9 micromolar.
ValidateCellML verifies this model as valid CellML with consistent units.
Model Structure
Nitric oxide (NO) plays an essential role in a diverse range of physiological and pathological processes, including acting as a potent vasodilator. NO can be synthesised in a reaction catalysed by the enzyme nitric oxide synthase (NOS), of which there are three isoforms: neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3). The substrates required for NO synthesis include: L-arginine (Arg), oxygen (O2), and nicotinamide adenine dinucleotide phosphate (NADPH). Once NO is synthesised in the vasculature, it diffuses into the smooth muscle of the blood vessel walls, resulting in muscle relaxation and vasodilation. As such, NO derived from NOS3 has been considered as the main regulator of vascular tone. However, despite its physiological importance, there is a general lack of data on NO production and how its distribution changes around arterioles under different oxygen conditions, mainly due to experimental limitations.
In the study described here in CellML, Kejing Chen and Aleksander Popel produced a mathematical model to capture the characteristics of the biochemical pathway of neuronal nitric oxide synthase (NOS1). A schematic diagram of the reactions included in this model is outlined in the figure below.
model diagram
Schematic diagram of the mathematical model. Pathway of NO release and transport catalysed by neuronal nitric oxide synthase ((NOS1), here represented by the heme iron (Fe)). The heme ion of NOS1 binds L-arginine (Arg), hydroxyl-L-arginine (NOHA), and oxygen (O2), and undergoes a series of oxygenation and reduction reactions.
The complete original paper reference is cited below:
Vascular and perivascular nitric oxide release and transport: biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3), Kejing Chen and Aleksander S. Popel, 2007,
Free Radical Biology and Medicine
, 42, 811-822. (Full text and PDF versions of the article are available to journal subscribers on the Free Radical Biology and Medicine website.) PubMed ID: 17320763
Fe3
neuronal nitric oxide synthase (heme iron 3+)
$\frac{d \mathrm{Fe3}}{d \mathrm{time}}=\mathrm{k\_1}\mathrm{Fe3\_Arg}+\mathrm{k13}\mathrm{Fe3\_NO}+\mathrm{k12}\mathrm{Fe2\_NO}\mathrm{O2}-\mathrm{k1}\mathrm{Arg}\mathrm{Fe3}+\mathrm{k2}\mathrm{Fe3}$
Fe3_Arg
neuronal nitric oxide synthase (heme iron 3+) bound to L-arginine
$\frac{d \mathrm{Fe3\_Arg}}{d \mathrm{time}}=\mathrm{k1}\mathrm{Fe3}\mathrm{Arg}-\mathrm{k\_1}\mathrm{Fe3\_Arg}+\mathrm{k3}\mathrm{Fe3\_Arg}$
Fe2
neuronal nitric oxide synthase (heme iron 2+)
$\frac{d \mathrm{Fe2}}{d \mathrm{time}}=\mathrm{k2}\mathrm{Fe3}+\mathrm{k\_4}\mathrm{Fe2\_Arg}-\mathrm{k4}\mathrm{Fe2}\mathrm{Arg}$
Fe2_Arg
neuronal nitric oxide synthase (heme iron 2+) bound to L-arginine
$\frac{d \mathrm{Fe2\_Arg}}{d \mathrm{time}}=\mathrm{k3}\mathrm{Fe3\_Arg}+\mathrm{k\_5}\mathrm{Fe3\_O2\_Arg}+\mathrm{k4}\mathrm{Fe2}\mathrm{Arg}-\mathrm{k5}\mathrm{Fe2\_Arg}\mathrm{O2}+\mathrm{k\_4}\mathrm{Fe2\_Arg}$
Fe3_O2_Arg
oxidised neuronal nitric oxide synthase (heme iron 3+) bound to L-arginine
$\frac{d \mathrm{Fe3\_O2\_Arg}}{d \mathrm{time}}=\mathrm{k5}\mathrm{Fe2\_Arg}\mathrm{O2}-\mathrm{k6}\mathrm{Fe3\_O2\_Arg}+\mathrm{k\_5}\mathrm{Fe3\_O2\_Arg}$
Fe3_NOHA
neuronal nitric oxide synthase (heme iron 3+) bound to hydroxyl-L-arginine
$\frac{d \mathrm{Fe3\_NOHA}}{d \mathrm{time}}=\mathrm{k6}\mathrm{Fe3\_O2\_Arg}-\mathrm{k7}\mathrm{Fe3\_NOHA}$
Fe2_NOHA
neuronal nitric oxide synthase (heme iron 2+) bound to hydroxyl-L-arginine
$\frac{d \mathrm{Fe2\_NOHA}}{d \mathrm{time}}=\mathrm{k7}\mathrm{Fe3\_NOHA}+\mathrm{k\_9}\mathrm{Fe3\_O2\_NOHA}+\mathrm{k8}\mathrm{Fe2}\mathrm{NOHA}-\mathrm{k\_8}\mathrm{Fe2\_NOHA}+\mathrm{k9}\mathrm{Fe2\_NOHA}\mathrm{O2}$
Fe3_O2_NOHA
oxidised neuronal nitric oxide synthase (heme iron 3+) bound to hydroxyl-L-arginine
$\frac{d \mathrm{Fe3\_O2\_NOHA}}{d \mathrm{time}}=\mathrm{k9}\mathrm{Fe2\_NOHA}\mathrm{O2}-\mathrm{k10}\mathrm{Fe3\_O2\_NOHA}+\mathrm{k\_9}\mathrm{Fe3\_O2\_NOHA}$
Fe3_NO
neuronal nitric oxide synthase (heme iron 3+) bound to nitric oxide
$\frac{d \mathrm{Fe3\_NO}}{d \mathrm{time}}=\mathrm{k10}\mathrm{Fe3\_O2\_NOHA}-\mathrm{k13}\mathrm{Fe3\_NO}+\mathrm{k11}\mathrm{Fe3\_NO}$
Fe2_NO
neuronal nitric oxide synthase (heme iron 2+) bound to nitric oxide
$\frac{d \mathrm{Fe2\_NO}}{d \mathrm{time}}=\mathrm{k11}\mathrm{Fe3\_NO}-\mathrm{k12}\mathrm{Fe2\_NO}\mathrm{O2}$
NO
nitric oxide
$\frac{d \mathrm{NO}}{d \mathrm{time}}=\mathrm{k13}\mathrm{Fe3\_NO}\frac{d \mathrm{NO}}{d \mathrm{time}}=\mathrm{dNOdt}$
$\frac{d \mathrm{citrulline}}{d \mathrm{time}}=\mathrm{k10}\mathrm{Fe3\_O2\_NOHA}$
NO3
nitrate
$\frac{d \mathrm{NO3}}{d \mathrm{time}}=\mathrm{k12}\mathrm{Fe2\_NO}\mathrm{O2}$
NOHA
hydroxyl-L-arginine
$\frac{d \mathrm{NOHA}}{d \mathrm{time}}=\mathrm{k\_8}\mathrm{Fe2\_NOHA}-\mathrm{k8}\mathrm{Fe2}\mathrm{NOHA}$
nitric oxide
nitric oxide synthase
signal transduction
cerebral aneurysm
nitric oxide
nitric oxide synthase
signal transduction
cerebral aneurysm
Chen and Popel's 2007 mathematical model of vascular and perivascular nitric oxide release and transport, which includes biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3).
10
Catherine Lloyd
James Lawson
2007-09-03T15:03:09+12:00
c.lloyd@auckland.ac.nz
Vascular and perivascular nitric oxide release and transport: biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3)
42
811
822
The University of Auckland
The Bioengineering Institute
keyword
2007-08-29T00:00:00+00:00
Aleksander
Popel
S
Free Radical Biology and Medicine
James
Lawson
Richard
Catherine
Lloyd
May
2007-03-15
The University of Auckland, Bioengineering Institute
This model is known to run in PCEnv and COR and is known to be mathematically consistent with the publication it was based on. This model has had an equation added to allow it to reproduce Figure 2 of the publication
Kejing
Chen
Added equation defining time differential of NO production (i.e. production rate of NO by NOS1 in uM of NO/second). This was done to allow the model to reproduce figure 2 of the publicatio
17320763
This is a CellML description of Chen and Popel's 2007 mathematical model of vascular and perivascular nitric oxide release and transport, which includes biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3).