5-METHYLTETRAHYDROFOLATE, THE ACTIVE FORM OF FOLIC-ACID, RESTORES ENDOTHELIAL FUNCTION IN FAMILIAL HYPERCHOLESTEROLEMIA

Background-Impaired nitric oxide (NO) activity is an early event in th e pathogenesis of cardiovascular disease, resulting from either reduce d NO formation or increased NO degradation. Administration of tetrahyd robiopterin (BH,), an essential cofactor for NO production, could rest ore NO activity in familial hypercholesterolemia (FH). Because folates have been suggested to stimulate endogenous BH4 regeneration, we hypo thesized that administration of 5-methyltetrahydrofolate (5-MTHF, the active circulating form of folate) might improve NO formation in FH. M ethods and Results-We studied the effects of 5-MTHF on NO bioavailabil ity in vivo in 10 patients with FH and 10 matched control subjects by venous occlusion plethysmography, using serotonin and nitroprusside as endothelium-dependent and -independent vasodilators. In vitro, we inv estigated the effect of 5-MTHF on NO production by recombinant endothe lial NO synthase (eNOS) by use of [H-3]arginine to [H-3]citrulline con version. We also studied the effects of 5-MTHF on superoxide generatio n by eNOS and xanthine oxidase (XO) by use of lucigenin chemiluminesce nce. The impaired endothelium-dependent vasodilation in FH (63% versus 90% in control subjects) could be reversed by coinfusion of 5-MTHF (1 17% vasodilation), whereas 5-MTHF had no significant effect on endothe lium-dependent vasodilation in control subjects. 5-MTHF did not influe nce basal forearm vasomotion or endothelium-independent vasodilation. 5-MTHF had no direct effect on in vitro NO production by eNOS. However , we did observe a dose-dependent reduction in both eNOS- and XO-induc ed superoxide generation. Conclusions-These results show that the acti ve form of folic acid restores in vivo endothelial function in FH. It is suggested from our in vitro experiments that this effect is due to reduced catabolism of NO.