5-Methyltetrahydrofolate, the Active Form of Folic Acid, Restores Endothelial Function in Familial Hypercholesterolemia

Abstract

Background-Impaired nitric oxide (NO) activity is an early event in the pathogenesis of cardiovascular disease, resulting from either reduced NO formation or increased NO degradation. Administration of tetrahydrobiopterin (BH 4 ), an essential cofactor for NO production, could restore NO activity in familial hypercholesterolemia (FH). Because folates have been suggested to stimulate endogenous BH 4 regeneration, we hypothesized that administration of 5-methyltetrahydrofolate (5-MTHF, the active circulating form of folate) might improve NO formation in FH. Methods and Results-We studied the effects of 5-MTHF on NO bioavailability in vivo in 10 patients with FH and 10 matched control subjects by venous occlusion plethysmography, using serotonin and nitroprusside as endotheliumdependent and -independent vasodilators. In vitro, we investigated the effect of 5-MTHF on NO production by recombinant endothelial NO synthase (eNOS) by use of [ 3 H]arginine to [ 3 H]citrulline conversion. We also studied the effects of 5-MTHF on superoxide generation by eNOS and xanthine oxidase (XO) by use of lucigenin chemiluminescence. The impaired endothelium-dependent vasodilation in FH (63% versus 90% in control subjects) could be reversed by coinfusion of 5-MTHF (117% vasodilation), whereas 5-MTHF had no significant effect on endothelium-dependent vasodilation in control subjects. 5-MTHF did not influence 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-induced superoxide generation. Conclusions-These results show that the active 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. (Circulation. 1998;97:237-241.)

Reduction in plasma total homocysteine through increasing folate intake in healthy individuals is not associated with changes in measures of antioxidant activity or oxidant damage

“…There has been recent interest in a potential antioxidant role for folate independent of its homocysteine-lowering effect. This has been demonstrated in experimental systems in vitro (Usui et al, 1999), and at a very high concentration in vivo (Wilmink et al, 2000;Verhaar et al, 1998;Nakano et al, 2002). There is no evidence from this study that physiological intakes of folate have a measurable antioxidant effect in vivo.…”

Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering

“…Oral folic acid supplementation has been shown to improve brachial artery endothelial function in subjects with hyperhomocysteinemia, 11,12 familial hypercholesterolemia, 13,14 and coronary artery disease. [7][8][9][10] However, when we started our study, there was limited information in subjects with diabetes mellitus.…”

“…[1][2][3]6 We and others have demonstrated that folic acid can significantly improve endothelium-dependent vasodilation in patients with coronary artery disease, [7][8][9][10] asymptomatic hyperhomocysteinemia, 11,12 and asymptomatic familial hypercholesterolemia. 13,14 While this benefit may in part be related to homocysteinelowering, 7,8 other studies suggest that the restoration of endothelial function by folates may be independent of its homocysteine-lowering effect. 10,14 In fact, 5-methyltetrahydrofolate, the active metabolite of folic acid, may have direct effects on uncoupled eNOS, which results in increased release of NO and decreased release of superoxide anion.…”

“…10,14 In fact, 5-methyltetrahydrofolate, the active metabolite of folic acid, may have direct effects on uncoupled eNOS, which results in increased release of NO and decreased release of superoxide anion. 13,15,16 Thus, there may be a rationale for considering the use of folates to restore NO availability in situations such as diabetes where there is a relative deficiency of active tetrahydrobiopterin. Indeed, van Etten et al 17 demonstrated that an acute arterial infusion of 5-methyltetrahydrofolate could restore impaired endothelium-dependent vasodilatation as assessed by forearm plethysmography in patients with type 2 diabetes.…”

Plasma homocysteine concentration and blood pressure in healthy Iranian adults: the Tehran Homocysteine Survey (2003–2004)

“…[22][23][24] The protective effect of these B vitamins may be partly explained by mechanisms independent of Hcy, as suggested by several recent studies, 25 and the B vitamins may themselves affect BP. 26,27 Observations that Hcylowering therapies with folic acid-based treatments have been followed by decreases in BP raise the possibility that the link between Hcy and BP is causal, which is important since Hcy levels can easily be lowered by folic acid-based regimens. 28 The purpose of this study was to determine the relationship of Hcy with BP, and other cardiovascular disease risk factors, including body mass index (BMI), glucose, lipids and smoking status on the one hand and between Hcy nutritional determinants and hypertension in a healthy adult Iranian population as part of the 'Tehran Homocysteine Survey' on the other hand (Table 1).…”