42 - How does ascorbate improve endothelial dysfunction?

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Low levels of ascorbate (ASC, reduced form of vitamin C) are associated with several diseases linked to increased oxidative stress, such as cancer, diabetes, HIV, sepsis and other cardiovascular diseases (CVD’s). In these diseases, either the systemic or localized cellular ASC deficiency is reported as a cause for endothelial dysfunction (ED). It is well established that ED is primarily caused due to reduction in nitric oxide (NO) and increase in oxidative stress. The synthesis and bioavailability of NO are sensitive to ASC, yet the mechanism by which ASC improves ED is unclear. In the present study, we examined putative mechanisms that might account for the ability of ASC to increase NO bioavailability and thus improve ED. Since the biochemical interactions among the reactive species are complex and rapid, we used the computational modeling approaches to understand these mechanistic interactions. In the present study, a single cell computational model was developed that involves eNOS biochemical pathway, downstream reactions involving NO and various reactive oxygen and nitrogen species, cellular oxidative stress and ASC. Using this model, we analyzed the role of ASC in ED by determining, i) the NO bioavailability; ii) optimal levels of intracellular ASC required to improve ED and iii) analyzing interactions of ASC with BH4 and other reactive species including O2•– and ONOO–. The model results show, (i) oxidative stress decreased the NO production and biopterin ratio and increased O2•– production; (ii) ASC supplementation in the range of 10 – 100 µM improved NO production rate, BH4 bioavailability and biopterin ratio under varying oxidative stress conditions; (iii) scavenging of O2•– and ONOO– by ASC was negligible. This study suggests that ASC improves ED by enhancing BH4 bioavailability and stabilizing eNOS under oxidative stress conditions.