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Abstract
In endothelial cell dysfunction, the uncoupling of eNOS results in higher superoxide (O2•−) and lower NO production and a reduction in NO availability. Superoxide reacts with NO to form a potent oxidizing agent peroxynitrite (ONOO−) resulting in nitrosative and nitroxidative stresses and dismutates to form hydrogen peroxide. Studies have shown superoxide dismutase (SOD) plays an important role in reduction of O2•− and ONOO− during eNOS uncoupling. However, the administration or over-expression of SOD was ineffective or displayed deleterious effects in some cases. An understanding of interactions of the two enzyme systems eNOS and SOD is important in determining endothelial cell function. We analyzed complex biochemical interactions involving eNOS and SOD in eNOS uncoupling. A computational model of biochemical pathway of the eNOS-related NO and O2•− production and downstream reactions involving NO, O2•−, ONOO−, H2O2 and SOD was developed. The effects of SOD concentration on the concentration profiles of NO, O2•−, ONOO− and H2O2 in eNOS coupling/uncoupling were investigated. The results include (i) SOD moderately improves NO production and concentration during eNOS uncoupling, (ii) O2•− production rate is independent of SOD concentration, (iii) Increase in SOD concentration from 0.1 to 100 μM reduces O2•− concentration by 90% at all [BH4]/[TBP] ratios, (iv) SOD reduces ONOO− concentration and increases H2O2 concentration during eNOS uncoupling, (v) Catalase can reduce H2O2 concentration and (vi) Dismutation rate by SOD is the most sensitive parameter during eNOS uncoupling. Thus, SOD plays a dual role in eNOS uncoupling as an attenuator of nitrosative/nitroxidative stress and an augmenter of oxidative stress.