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Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 12/15/2000 Publication Date: N/A Citation: N/A Interpretive Summary: A moderate elevation of circulating homocysteine was reported to be common in patients with cardiovascular disease, and a moderate-to-high elevation of homocysteine (31-160 remold) was considered a risk factor leading to the progress of cardiovascular disease. In fact, the high level of homocysteine has been reported to affect multi factorially both the vascular wall structure and the blood coagulation system. Several Vitamin C intervention studies have been performed to determine its long-term effect on cardiovascular disease. The results are positive, but lacking the mechanism underlining the effect of vitamin C. In order to illustrate beneficial effects of vitamin C on cardiovascular disease, there is an urgent need to elucidate the underlined mechanism. The data in this paper clearly demonstrate that homocysteine reduces dehydroascorbic acid (an oxidized form of vitamin C) to vitamin C and that homocysteine is oxidized to homocystine in the process of reducing dehydroascorbic acid. On basis of these data, a mechanism was proposed to explain the beneficial effect of vitamin C on endothelial cells via reducing total amount of extracellular homocysteine (an independent risk factor for heart diseases). This information will provide scientists and physicians germane understanding of an underlined mechanism of beneficial effect of vitamin C, thereby applying vitamin C fortified diets to attenuate a pathological condition of chronic cardiovascular disease. Technical Abstract: To determine the reductive process of extra cellular dehydroascorbic acid (DHA), molecules (homocysteine, homocysteine thiolactone, methionine, cysteine, homoserine, and alpha-lipoic acid) were tested to identify those with the potential to reduce DHA to ascorbic acid (AA). Homocysteine (Hey) was the most potent of the molecules tested. The efficacy of Hcy was compared with that of other molecules able to reduce DHA (reduced glutathione [GSH] and cysteine [Cy]); even though all three molecules were able to reduce DHA, GSH and Cy could not reduce DHA to AA at concentrations lower than 100 1lmol/l,and only less than 5% DHA was reduced to AA at concentrations of 200-300 1lmol/l. In contrast, Hcy reduced DHA to AA stoichiometrically at concentrations as low as I O 1lmol/l.In Jurkat and U937 cells, the increasing concentrations of extracellular Hcy suppressed intracellular dehydroascorbic acid uptake, indicating that extracellular reduction of DHA by Hcy leads to decreasing extra cellular DHA available for its intracellular uptake. Simultaneous oxidation and reduction of Hcy and DHA were accelerated extracellular in the presence of quercetin, an inhibitor of DHA uptake, suggesting that extracellular ascorbic acid concentration increased via blocking DHA uptake by quercetin and reducing extracellular DHA by Hcy. This effect of Hcy on DHA reduction was confirmed with human umbilical vein endothelial cells. A mechanism is proposed to illustrate a possible beneficial effect of vitamin C on endothelial cells. |
