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Impact of SOD on Endothelial Cell Free Radical Distribution during eNOS Uncoupling

Uncoupling of endothelial nitric oxide synthase (eNOS) results in a lower NO production and an increase in O2•− production from eNOS. The excess O2•− produced in the endothelial cells either reacts with the reduced NO available to from peroxynitrite (ONOO−) or gets dismutated by the enzyme superoxide dismutase (SOD) to form another oxidizing species H2O2. The excess H2O2 is scavenged by certain enzymes. It has been reported that oxidative stress reduces the activity of SOD and H2O2 scavenging enzymes causing excess build up of H2O2 and ONOO− in the endothelial cells. In this study, we quantify the contribution of eNOS uncoupling and SOD concentration on endothelial cell based H2O2 and ONOO− concentration for functional and dysfunctional endothelium. A single cell based computational model involving the biochemical pathways of eNOS and the reactions involving NO, O2•− and ONOO− was developed. The extent of endothelial functionality was defined by biopterin ratio ([BH4]/[TBP]). The results show that (1) both ONOO− and H2O2 concentration vary significantly with SOD concentration at all biopterin ratios and (2) for a given SOD concentration, H2O2 concentration increased by 3 orders of magnitude on transition from functional to chronic dysfunctional endothelium. The results show that eNOS uncoupling is a significant contributor to oxidative stress and the limitations of SOD to reduce it. Supported by NIH R01 HL084337.