© 2000 American Heart Association, Inc.
Molecular Medicine |
Folic Acid Reverts Dysfunction of Endothelial Nitric Oxide Synthase
From the Departments of Vascular Medicine (E.S.G.S., M.Y., R.G., T.J.R.) and Nephrology (P.B.), University Hospital Utrecht, The Netherlands; Debye Institute (E.E.v.F.), University Utrecht, The Netherlands; and Department of Pediatrics, First Faculty of Medicine (P.M.), Charles University, Prague, Czech Republic.
Correspondence to Dr E.S.G. Stroes, Department of Vascular Medicine, F 03.226, University Hospital Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail e.stroes{at}digd.azu.nl
Abstract—5-Methyltetrahydrofolate (MTHF), the active form of folic acid, has been reported to restore NO status in hypercholesterolemic patients. The mechanism of this effect remains to be established. We assessed the effects of L- and D-MTHF on tetrahydrobiopterin (BH4)–free and partially BH4-repleted endothelial NO synthase (eNOS). Superoxide production of eNOS and the rate constants for trapping of superoxide by MTHF were determined with electron paramagnetic resonance using 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO) as spin trap for superoxide. NO production was measured with [3H]arginine–citrulline conversion or nitrite assay. The rate constants for scavenging of superoxide by L- and D-MTHF were similar, 1.4x104 ms–1. In BH4-free eNOS, L- and D-MTHF have no effect on enzymatic activity. In contrast, in partially BH4-repleted eNOS, we observe a 2-fold effect of MTHF on the enzymatic activity. First, superoxide production is reduced. Second, NO production is enhanced. In cultured endothelial cells, a similar enhancement of NO production is induced by MTHF. In the present study, we show direct effects of MTHF on the enzymatic activity of NO synthase both in recombinant eNOS as well as in cultured endothelial cells, which provides a plausible explanation for the previously reported positive effects of MTHF on NO status in vivo.
Key Words: folic acid • nitric oxide • nitric oxide synthase • tetrahydrobiopterin • electron spin resonance
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