How does ascorbate improve endothelial dysfunction? - A computational analysis

• Published in: Free radical biology & medicine Vol. 165; pp. 111 - 126
• Main Authors: Panday, Sheetal, Kar, Saptarshi, Kavdia, Mahendra
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2021
• Subjects: Antioxidants - pharmacology; Ascorbic Acid - pharmacology; Biopterins; Endothelial cell computational model; Endothelium, Vascular; eNOS uncoupling; Glutathione; Humans; Kinetic model; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Peroxynitrite; Superoxide; Tetrahydrobiopterin; Vascular Diseases; Vitamin C; Oxidative stress; Kinetic model; Endothelial cell computational model; Peroxynitrite; Tetrahydrobiopterin; Vitamin C; Superoxide; eNOS uncoupling; Glutathione
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2021.01.031

Low levels of ascorbate (Asc) are observed in cardiovascular and neurovascular diseases. Asc has therapeutic potential for the treatment of endothelial dysfunction, which is characterized by a reduction in nitric oxide (NO) bioavailability and increased oxidative stress in the vasculature. However, the potential mechanisms remain poorly understood for the Asc mitigation of endothelial dysfunction. In this study, we developed an endothelial cell based computational model integrating endothelial cell nitric oxide synthase (eNOS) biochemical pathway with downstream reactions and interactions of oxidative stress, tetrahydrobiopterin (BH4) synthesis and biopterin ratio ([BH4]/[TBP]), Asc and glutathione (GSH). We quantitatively analyzed three Asc mediated mechanisms that are reported to improve/maintain endothelial cell function. The mechanisms include the reduction of •BH3 to BH4, direct scavenging of superoxide (O2•−) and peroxynitrite (ONOO−) and increasing eNOS activity. The model predicted that Asc at 0.1–100 μM concentrations improved endothelial cell NO production, total biopterin and biopterin ratio in a dose dependent manner and the extent of cellular oxidative stress. Asc increased BH4 availability and restored eNOS coupling under oxidative stress conditions. Asc at concentrations of 1–10 mM reduced O2•− and ONOO− levels and could act as an antioxidant. We predicted that glutathione peroxidase and peroxiredoxin in combination with GSH and Asc can restore eNOS coupling and NO production under oxidative stress conditions. Asc supplementation may be used as an effective therapeutic strategy when BH4 levels are depleted. This study provides detailed understanding of the mechanism responsible and the optimal cellular Asc levels for improvement in endothelial dysfunction.
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•Investigation of mechanisms of vitamin C in treatment of endothelial dysfunction.•Computational modeling of eNOS pathway, oxidative stress, biopterins & ascorbate.•0.1–100 μM ascorbate improves NO production, biopterin ratio & endothelial function.•Above 1 mM ascorbate scavenges O2.•− and ONOO− and reduces oxidative stress.•Combination of Asc & BH4 supplementation may considerably improve biopterin ratio.