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.
Moat
Stuart J
SJ
Department of Medical Biochemistry, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN, United Kingdom.
Clarke
Zoe L
ZL
Madhavan
Anil K
AK
Lewis
Malcolm J
MJ
Lang
Derek
D
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D004050:Ditiocarb / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005492:Folic Acid / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011817:Rabbits; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors; D013481:Superoxides / Q000378:metabolism; D013552:Swine; D014664:Vasodilation / Q000187:drug effects
D013481:Superoxides; D001708:Biopterins; C017226:7,8-dihydrobiopterin; D005492:Folic Acid; D004050:Ditiocarb; D013482:Superoxide Dismutase; C003402:sapropterin