Biochemical and functional interactions of methyltetrahydrofolate and homocysteine in vascular disease

In the last decade, hyperhomocysteinemia has become a well-established risk factor for vascular disease. Moderately elevated levels of the amino acid are associated with fatal and nonfatal cardiovascular disease. Although it is clear that elevations in homocysteine arise due to insufficiencies in the cofactors or enzymes involved in methionine metabolism, the mechanisms leading to the accelerated atherosclerosis in patients with hyperhomocysteinemia remains obscure.; The effects of high dose vitamin therapy were investigated in patients with renal failure. This study was expanded and the treatment effects were examined on the vitamin B₁₂ dependent variable methylmalonic acid and in patients stratified by the common MTHFR 677 C→T genotypes. High dose vitamin therapy while significantly lowering both homocysteine and MMA did not normalize levels irrespective of the MTHFR genotype.; The interactions between the MTHFR 677 C→T, MS 2756 A→G, and the MTRR 66 A→G genotypes and methionine metabolism in a number of patients with cardiovascular disease. The discovery of a highly significant decreased incidence of recurrent cardiovascular events in those heterozygous for the MS G allele prompted a more detailed investigation into the role of folate and homocysteine in endothelial dysfunction and more specifically the impact of folate and endothelial derived nitric oxide. Interestingly, folate attenuated oxidative stress and facilitated the release of nitric oxide both directly in vitro and indirectly in vivo.; The relationship between folate and nitric oxide prompted studies associating genetic polymorphism in eNOS and folate metabolism and their subsequent effect on blood pressure. We found a highly significant association between a very common point mutation in eNOS and blood pressure. Furthermore, the MS 2756 G allele may attenuate the effects of decreased nitric oxide production induced by the point mutation in eNOS. Lastly, using an animal model of hypertension it was determined that treatment with methylated folates improved endothelial dependent nitric oxide release in the small resistance vessels.; Taken together, these studies provide new evidence that folate is an important mediator of vascular function. In addition, the studies herein suggests that one of the mechanisms leading to the association between hyperhomocysteinemia and vascular disease may be attributed to folate status.