Abstract 1155: The Common Genetic Polymorphism C677T of Methyltetrahydrofolate Reductase Regulates Nitric Oxide Bioavailability and Vascular Superoxide Production via Modulation of eNOS Coupling in Human Vessels
Introduction: 5-methyl-tetrahydrofolate (5MTHF) administration improves endothelial nitric oxide synthase (eNOS) coupling in human vessels. However, it is unclear whether endogenous variations of vascular 5MTHF levels due to the functional 5MTHF-reductase (MTHFR) polymorphism C677T, has an impact on vascular function. We examined the effect of this polymorphism on vascular 5MTHF levels, NO bioavailability and eNOS coupling in human vessels.
Methods: The C677T polymorphism was determined in 200 patients undergoing coronary bypass surgery. Saphenous veins (SV) and internal mammary arteries (IMA) were obtained to determine vasomotor responses of SV to acetylcholine (ACh) ex-vivo, vascular O2-production (+/− eNOS inhibitor LNAME, by chemilumineschence) and vascular 5MTHF (by HPLC).
Results: The genotype distribution was CC:92(46%) CT:86(43%) and TT:22(11%). This polymorphism had a strong effect on vascular (Fig. a⇓) and plasma 5MTHF (CC:56.9±7.1, CT:32.4±2.4 and TT:24.5±4.29nM, p<0.001) and plasma total homocysteine (CC:10.2±0.3, CT:10.8±0.3 and TT:12.4±0.8 μM, p<0.05). Furthermore, the T allele was associated with lower vasomotor responses of SV to Ach (Fig. b⇓) higher vascular O2- (Fig. c⇓) and greater LNAME inhibitable O2- (Fig d⇓., suggesting eNOS uncoupling).
Conclusions: The C677T polymorphism of the MTHFR gene is a strong determinant of plasma and vascular 5MTHF, and has a significant effect on NO bioavailability and vascular redox state, by modifying eNOS coupling in human vessels.