Abstract 4416: Genetic Variability of Methyl-Tetrahydrofolate-Reductase Modifies eNOS Coupling in Human Arteries and Veins: Effects on Vascular Superoxide Generation and Nitric Oxide Bioavailability

Abstract

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. The C677T polymorphism was determined in 218 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). The genotype distribution was CC:100(46%) CT:94(43%) and TT:24(11%). This polymorphism had a strong effect on vascular (Fig. a ) and plasma 5MTHF (p<0.001). Furthermore, the T allele was associated with lower vasomotor responses of SV to Ach (Fig. b ) as well as higher vascular O2- (Fig. c ) and greater LNAME inhibitable O2- (Fig d ., suggesting eNOS uncoupling) in IMA segments. The C677T polymorphism on MTHFR gene is a strong determinant of vascular 5MTHF, and has a significant effect on NO bioavailability and vascular redox state, by modifying eNOS coupling in human vessels.