Endothelial NO and O2− production rates differentially regulate oxidative, nitroxidative, and nitrosative stress in the microcirculation

Abstract

Endothelial dysfunction causes an imbalance in endothelial NO and O2•− production rates and increased peroxynitrite formation. Peroxynitrite and its decomposition products cause multiple deleterious effects including tyrosine nitration of proteins, superoxide dismutase (SOD) inactivation and tissue damage. Studies have shown that peroxynitrite formation during endothelial dysfunction is strongly dependent on the NO and O2•− production rates. Previous experimental and modeling studies examining the role of NO and O2•− production imbalance on peroxynitrite formation showed different results in biological and synthetic systems. However, there is a lack of quantitative information about the formation and biological relevance of peroxynitrite in oxidative, nitroxidative and nitrosative stress conditions in the microcirculation. We developed a computational biotransport model to examine the role of endothelium NO and O2•− production on the complex biochemical NO and O2•− interactions in the microcirculation. We also modeled the effect of variability in SOD expression and activity during oxidative stress. The results showed that peroxynitrite concentration increased with increase in either O2•− to NO or NO to O2•− production rate ratios (QO2•−/QNO or QNO/QO2•−, respectively). The peroxynitrite concentrations were similar for both production rate ratios indicating that peroxynitrite related nitroxidative and nitrosative stresses may be similar in endothelial dysfunction or iNOS induced NO production. The endothelial peroxynitrite concentration increased with increase in both QO2•−/QNO or QNO/QO2•− ratios at SOD concentrations 0.1–100 μM. The absence of SOD may not mitigate the extent of peroxynitrite mediated toxicity as we predicted insignificant increase in peroxynitrite levels beyond QO2•−/QNO and QNO/QO2•−ratio of 1. The results support the experimental observations of biological systems and show that peroxynitrite formation increases with increase in either NO or O2•− production and excess NO production from iNOS or from NO donors during oxidative stress conditions does not reduce the extent of peroxynitrite mediated toxicity.

Centrally acting drug moxonidine decreases reactive oxygen species via inactivation of the phosphoinositide-3 kinase signaling in the rostral ventrolateral medulla in hypertensive rats

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Evaluation of cardiovascular biomarkers in patients with age-related wet macular degeneration

“…Similarly, several studies showed that NO also reacts with oxygen and superoxide anion to form nitrogen dioxide and peroxynitrite anion, which are known cytotoxic oxygen radicals 49. İncreased peroxynitrite concentration causes endothelial dysfunction 50. In another study examining NO in AMD, the NO levels were found to be lower in AMD patients than in controls, but the underlying mechanism was not described.…”

Induced peroxidase and cytoprotective enzyme expressions support adaptation of HUVECs to sustain subsequent H₂O₂ exposure

“…Using a systems biology approach, we showed that hyperglycemia induces the production of H 2 O 2 in human umbilical vein endothelial cells (HUVEC) (Patel et al, 2013). Additionally, the presence of high ROS levels are shown to promote a pro-oxidative redox response in endothelial cells (Coyle et al, 2006; Kar and Kavdia, 2013). Thus, the interplay between a high H 2 O 2 level and a dysfunctional endothelium can lead to a system wide progression of endothelial dysfunction in a feed-forward manner (Kar et al, 2012).…”