Elevated plasma homocysteine is a risk factor for cardiovascular disease. Homocysteine is thought to increase the risk of cardiovascular disease because it is able to increase endothelial dysfunction in the arteries and cause athrogenesis. However, it is unknown if this dysfunction occurs through the inhibition of nitric oxide formation by free radicals. Experimentally, elevated plasma homocysteine can be induced by methionine loading. In this process, the essential amino acid is ingested in large concentrations, and this increases endogenous production of homocysteine which raises plasma levels. Typical loading doses of methionine for this purpose are around 100mg/kg body weight. For example, researchers1 used a loading dose of methionine (100mg/kg body weight) to induce elevated plasma levels in 28 young subjects with normal plasma homocysteine levels (12µmol/L) in order to understand the vascular effects of elevated plasma homocysteine.
Chronic homocysteinaemia in the subjects was associated with increased oxidation of low density lipoprotein (LDL) cholesterol, endothelial dysfunction and elevated levels of endothelin-1. In acute tests 4 hours post methionine load, increased endothelin-1 was prevented by the simultaneous administration of vitamin C (2g) and vitamin E (800IU), but severe endothelial dysfunction and oxidised LDL remained. Endothelin-1 is a potent vasoconstrictor in human blood vessels and its synthesis is partly regulated by oxidation. These results suggest that the homocysteine induced endothelial dysfunction occurred independently of the presence of endothelin-1. This was confirmed in linear regression analysis, which showed that fasting homocysteine plasma levels were a predictor of baseline oxidised LDL, but not endothelin-1 levels. However, oxidised LDL was a predictor of elevated endothelin-1. Homocysteine may therefore increase endothelin-1 through indirect mechanisms, such as through increased levels of oxidised LDL.
Despite the suppression of oxidative stress and endothelin-1, antioxidant vitamins in this study failed to prevent severe homocysteine induced endothelial dysfunction. Therefore homocysteine induced endothelial dysfunction may occur through mechanisms other than those induced by oxidative stress alone. Current evidence suggests that elevated homocysteine can be controlled and reduced through supplementation of vitamin co-factors required for metabolism of homocysteine to other substances. These vitamins are folic acid and the cobalamins (vitamin B12) which are required for the conversion of homocysteine back to methionine, and vitamin B6 which is required for the conversion of homocysteine to cystathionine. Although antioxidant nutrients have proved effective at preventing free radical inhibition of nitric oxide in the endothelium, and at improving flow mediated dilation, it is still unclear as to whether homocysteine is involved in the inhibition of nitric oxide. These results suggest other mechanisms are present.
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