Premium
Role of Oxidative Stress and Tetrahydrobiopterin Synthesis on eNOS Catalyzed Nitric Oxide and Superoxide Production: A Computational Analysis
Author(s) -
Joshi Sheetal,
Kar Saptarshi,
Kavdia Mahendra
Publication year - 2015
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.29.1_supplement.1046.8
Subject(s) - biopterin , tetrahydrobiopterin , enos , oxidative stress , nitric oxide , chemistry , superoxide , oxidative phosphorylation , nitric oxide synthase type iii , nitric oxide synthase , biochemistry , medicine , endocrinology , biology , enzyme , organic chemistry
Endothelial nitric oxide synthase (eNOS) when bound to its co‐factor, tetrahydrobiopterin (BH 4 ) produce the vasodilator nitric oxide (NO). Oxidative stress in endothelial cells causes oxidation of BH 4 to dihydrobiopterin (BH 2 ). Binding of BH 2 to eNOS results in eNOS uncoupling and increased superoxide (O 2 •‐ ) production from eNOS catalysis. The extent of eNOS uncoupling depends on the biopterin ratio (the ratio of BH 4 to oxidized biopterins) in endothelial cells. Changes in endothelial cell oxidative stress levels can dynamically change the biopterin ratio by oxidation of BH 4 and by changes in activity of BH 4 producing enzyme GTPCH. There is a lack of understanding about the individual and collective effects of oxidative stress and BH 4 synthesis on biopterin ratio. In present study, we have developed a computational model for eNOS catalysis based on biochemical pathways of eNOS for NO and O 2 •‐ production. The model accounts for temporal changes in BH 4 concentration and biopterin ratio in addition to endothelial cell based oxidative stress and GTPCH based BH 4 production. The model predicts, increased endothelial cell oxidative stress causes eNOS catalyzed NO production to switch between steady state and oscillatory profiles. BH 4 production from augmented GTPCH activity could mitigate these oscillations and restore eNOS coupling only under moderate oxidative stress conditions. The results indicate that oxidative stress initiates temporal perturbations in biopterin ratio that switches eNOS from coupled to an uncoupled state at moderate and high oxidative stress conditions. The model results provide valuable quantitative information about the mechanisms promoting endothelial dysfunction.