Folic acid reverses endothelial dysfunction induced by inhibition of tetrahydrobiopterin biosynthesis

While folic acid has been shown to reverse endothelial dysfunction, the exact underlying mechanism remains elusive. Here, folic acid reversed both the endothelial dysfunction and increased production of superoxide following depletion of rabbit aortic ring tetrahydrobiopterin (BH₄) levels with 2,4-diamino-6-hydroxy-pyrimidine (DAHP) and N-acetyl-5-hydroxy-tryptamine (NAS). Incubation with l-nitroarginine methyl ester also attenuated the production of superoxide. DAHP and NAS reduced BH₄ concentrations in both aorta and cultured porcine aortic endothelial cells. Folic acid had no effect on BH₄ concentrations in either preparation. The superoxide anion scavenger Tiron but not folic acid reversed the endothelial dysfunction produced in aortic rings by inhibition of copper–zinc superoxide dismutase with diethyldithiocarbamic acid. Neither folic acid nor its metabolite 5-methyltetrahydrofolate prevented the in vitro oxidation of BH₄. This study demonstrates that folic acid reverses the endothelial dysfunction induced by BH₄ depletion independently of either the regeneration or stabilization of BH₄ or an antioxidant effect.