Abstract
Introduction Ascorbate (Asc) plays a critical role in maintaining of endothelial cell function through inhibition of apoptosis, stimulation of cell proliferation and improvement of endothelial derived NO bioavailability. A number of mechanisms including scavenging of free radicals, increase of tetrahydrobiopterin (BH4) levels and improving endothelial nitric oxide synthase (eNOS) coupling state have been proposed for Asc related NO bioavailability. Increase in cellular oxidative stress is associated with low cellular and plasma Asc levels. However, it is not certain which mechanisms and what optimal ascorbate levels are involved in the improvement of endothelial cell function in oxidative stress. Material and Methods In the present study, we developed a computational model that involves eNOS biochemical pathway, downstream reactions involving NO and various reactive oxygen and nitrogen species, cellular oxidative stress, BH4 synthesis and Asc supplementation. The model was simulated to investigate the changes in NO production and BH4 concentration with respect to Asc supplementation. Results and Discussions The model result shows that oxidative stress decreased the NO production. As shown in the below figure, supplementation of 50 µM Asc improved the NO production ~90 % under oxidative stress conditions, whereas Asc did not change NO production in control conditions (Figure A). Asc increased BH4 concentration in both control and oxidative stress condition (Figure B). This suggests Asc role in increasing BH4 bioavailability and keeping eNOS in coupled state. Experimental studies also confirm the role of ascorbate in replenishing the total antioxidant system of endothelial cells. Conclusion Our model result provides proof for the suggested role of Asc in replenishing BH4 and making it available for eNOS coupling. The results from this study provide quantitative understating of the role of ascorbate in the endothelial dysfunction and vascular diseases.
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