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A kinetic model of endothelial dysfunction from the NOS NO synthesis biochemical pathway
Author(s) -
Kar Saptarshi,
Kavdia Mahendra
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.602.10
Subject(s) - enos , superoxide , tetrahydrobiopterin , peroxynitrite , chemistry , biopterin , superoxide dismutase , nitric oxide , nitric oxide synthase , medicine , endocrinology , endothelium , oxidative stress , endothelial dysfunction , biochemistry , endothelial nos , enzyme , biology , organic chemistry
Endothelial nitric oxide synthase (enos) under the influence of shear stress due to blood flow and agonist produces the vasorelaxant nitric oxide (NO). In hyperglycemia, hypertension and hypercholesterolemia, enos uncouples and produces superoxide instead of NO, leading to endothelial dysfunction. One of the key events in the process of endothelial dysfunction involves reduction of enos co‐factor tetrahydrobiopterin (BH4) with respect to dihydrobiopterin (BH2). However, it is not known how this reduction affects NO/superoxide synthesis by enos. In this study, a mathematical kinetic model for biochemical pathways of enos was developed that accounts for both the normal and endothelial dysfunctional state. The effect of the biopterin ratio (BH2:BH4) and kinetic parameters on NO/superoxide synthesis was analyzed. The results predicted that an increase in BH2:BH4 ratio leads to a significant decrease in production of NO and increase in production of superoxide and peroxynitrite. The model also provides a range of kinetic parameters for NOS biochemical pathways over which significant superoxide formation occurs. In addition, superoxide dismutase significantly affects the concentrations of NO, superoxide and peroxynitrite. These results have implications for understanding NOS uncoupling related oxidative stress. Supported by NIH R01 HL084337.