RESUMEN
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.
Asunto(s)
Biopterinas/análogos & derivados , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Ácido Fólico/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Biopterinas/antagonistas & inhibidores , Biopterinas/metabolismo , Células Cultivadas , Ditiocarba/farmacología , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Técnicas In Vitro , Masculino , Conejos , Superóxido Dismutasa/antagonistas & inhibidores , Superóxidos/metabolismo , Porcinos , Vasodilatación/efectos de los fármacosRESUMEN
Evidence reported from numerous clinical studies over the past decade has revealed an association between increased plasma total homocysteine (tHcy) concentrations and cardiovascular disease (CVD). In addition, epidemiological studies have identified an inverse association between blood folate concentrations, folate intake and cardiovascular endpoints, that are independent of homocysteine. Folic acid supplementation can lower plasma tHcy concentrations safely and inexpensively. Furthermore, folic acid can reverse endothelial dysfunction observed in patients with CVD. This reversal in endothelial dysfunction with folic acid has been shown to be independent of plasma tHcy lowering, suggesting that folate has pleiotropic effects on the vasculature other than homocysteine lowering. In vitro evidence demonstrates that 5-methyltetrahydrofolate (5MeTHF) the main circulating metabolite of folate, can increase nitric oxide production and can directly scavenge superoxide radicals. The potential beneficial role of folic acid supplements on vascular disease are currently being tested in randomized placebo controlled studies.
