MTHFR 677 C > T Polymorphism Reveals Functional Importance for
5-Methyltetrahydrofolate, Not Homocysteine, in Regulation of Vascular
Redox State and Endothelial Function in Human Atherosclerosis
Background-The role of circulating homocysteine as an atherosclerosis
risk factor has recently been questioned. However,
5-methyl-tetrahydrofolate (5-MTHF), the circulating metabolite of folic
acid participating in homocysteine metabolism, has direct effects on
vascular function. We sought to distinguish the effects of plasma versus
vascular tissue 5-MTHF and homocysteine on vascular redox and
endothelial nitric oxide bioavailability in human vessels.
Methods and Results-We used the methyl tetrahydrofolate reductase
(MTHFR) gene polymorphism 677C>T as a model of chronic exposure of the
vascular wall to varying 5-MTHF levels in 218 patients undergoing
coronary artery bypass graft surgery. Vascular superoxide, vascular
5-MTHF, and total homocysteine were determined in saphenous veins and
internal mammary arteries obtained during surgery. Nitric oxide
bioavailability was evaluated by organ bath studies on saphenous vein
rings. MTHFR genotype was a determinant of vascular 5-MTHF (not vascular
homocysteine). Both MTHFR genotype and vascular 5-MTHF were associated
with vascular nitric oxide bioavailability and superoxide generated by
uncoupled endothelial nitric oxide synthase. In contrast, vascular
homocysteine was associated only with NADPH-stimulated superoxide.
Conclusions-Genetic polymorphism 677 C>T on MTHFR affects vascular
5-MTHF (but not homocysteine) and can be used as a model to distinguish
the chronic effects of vascular 5-MTHF from homocysteine on vascular
wall. Vascular 5-MTHF, rather than plasma or vascular homocysteine, is a
key regulator of endothelial nitric oxide synthase coupling and nitric
oxide bioavailability in human vessels, suggesting that plasma
homocysteine is an indirect marker of 5-MTHF rather than a primary
regulator of endothelial function. (Circulation. 2009; 119: 2507-2515.
