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(Circulation. 2006;114:1193-1201.)
© 2006 American Heart Association, Inc.

Vascular Medicine

5-Methyltetrahydrofolate Rapidly Improves Endothelial Function and Decreases Superoxide Production in Human Vessels

Effects on Vascular Tetrahydrobiopterin Availability and Endothelial Nitric Oxide Synthase Coupling

Charalambos Antoniades, MD, PhD^*; Cheerag Shirodaria, MRCP^*; Nicholas Warrick, BSc, PhD; Shijie Cai, MD, PhD; Joseph de Bono, MRCP; Justin Lee, MRCP; Paul Leeson, PhD, MRCP; Stefan Neubauer, MD, FRCP; Chandi Ratnatunga, FRCS; Ravi Pillai, FRCS; Helga Refsum, MD, PhD; Keith M. Channon, MD, FRCP

From the Departments of Cardiovascular Medicine and Cardiac Surgery (C.A., C.S., N.W., S.C., J.d.B., J.L., P.L., S.N., C.R., R.P., K.M.C.), John Radcliffe Hospital, and Oxford Centre for Gene Function (H.R.), University Laboratory of Physiology, University of Oxford, Oxford, United Kingdom.

Correspondence to Professor Keith M. Channon, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom. E-mail keith.channon{at}cardiov.ox.ac.uk

Received January 10, 2006; revision received June 14, 2006; accepted June 23, 2006.

Background— The circulating form of folic acid, 5-methyltetrahydrofolate (5-MTHF), may have beneficial effects on endothelial function; however, its mechanisms of action remain uncertain. Decreased nitric oxide (NO) bioavailability and increased vascular superoxide production in vascular disease states are due in part to endothelial NO synthase (eNOS) uncoupling related to deficiency of the eNOS cofactor tetrahydrobiopterin (BH₄), but whether this mechanism is important in human atherosclerosis and represents a rational therapeutic target remains unclear. We hypothesized that 5-MTHF would improve endothelial function by decreasing superoxide and peroxynitrite production and by improving eNOS coupling, mediated by BH₄ availability.

Methods and Results— Vascular superoxide/peroxynitrite production and vasomotor responses to acetylcholine and bradykinin were determined in saphenous veins and internal mammary arteries from 117 patients undergoing CABG. The effects of 5-MTHF were examined ex vivo (n=61) by incubating vessels with 5-MTHF (1 to 100 µmol/L) and in vivo by intravenous infusion of 5-MTHF or placebo before vessel harvest (n=56). 5-MTHF improved NO-mediated endothelium-dependent vasomotor responses and reduced vascular superoxide, both ex vivo and in vivo. These changes were not explained by direct superoxide scavenging by 5-MTHF in vitro or by changes in plasma total homocysteine in vivo. Rather, 5-MTHF was a strong peroxynitrite scavenger and increased vascular BH₄ and the BH₄/total biopterin ratio. Furthermore, 5-MTHF reversed eNOS uncoupling, as assessed by N^G-nitro-L-arginine methyl ester–inhibitable superoxide production, increased the eNOS dimer:monomer ratio, and enhanced eNOS activity.

Conclusions— 5-MTHF has beneficial effects on endothelial function and vascular superoxide production in human atherosclerosis, by preventing peroxynitrite-mediated BH₄ oxidation and improving eNOS coupling.

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