From the Departments of Nephrology and Hypertension (M.C.V., T v D.,
H.A.K., T.J.R.) and Clinical Chemistry (R.M.F.W.), University Hospital
Utrecht, and Department of Vascular Medicine (J.J.P.K.), University Medical
Centre Amsterdam, Netherlands.
Correspondence to Ton J. Rabelink, Department of Nephrology and Hypertension, University Hospital Utrecht, Heidelberglaan 100, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail T.Rabelink{at}digd.azu.nl
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 (BH4), an essential cofactor for NO
production, could restore NO activity in familial
hypercholesterolemia (FH). Because folates have
been suggested to stimulate endogenous BH4
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
endothelium-dependent and -independent vasodilators. In
vitro, we investigated the effect of 5-MTHF on NO production by
recombinant endothelial NO synthase (eNOS) by use of
[3H]arginine to [3H]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.
© 1998 American Heart Association, Inc.
Brief Rapid Communications
5-Methyltetrahydrofolate, the Active Form of Folic Acid, Restores Endothelial Function in Familial Hypercholesterolemia
Key Words: endothelium • endothelium-derived factors • hypercholesterolemia • folates
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