title: Folic Acid Promotes Recycling of Tetrahydrobiopterin and Protects Against Hypoxia-Induced Pulmonary Hypertension by Recoupling Endothelial Nitric Oxide Synthase.
abstract: OBJECTIVE
  Nitric oxide (NO) derived from endothelial NO synthase (eNOS) has been implicated in the adaptive response to hypoxia. An imbalance between 5,6,7,8-tetrahydrobiopterin (BH4) and 7,8-dihydrobiopterin (BH2) can result in eNOS uncoupling and the generation of superoxide instead of NO. Dihydrofolate reductase (DHFR) can recycle BH2 to BH4, leading to eNOS recoupling. However, the role of DHFR and eNOS recoupling in the response to hypoxia is not well understood. We hypothesized that increasing the capacity to recycle BH4 from BH2 would improve NO bioavailability as well as pulmonary vascular remodeling (PVR) and right ventricular hypertrophy (RVH) as indicators of pulmonary hypertension (PH) under hypoxic conditions.
  
  
  RESULTS
  In human pulmonary artery endothelial cells and murine pulmonary arteries exposed to hypoxia, eNOS was uncoupled as indicated by reduced superoxide production in the presence of the nitric oxide synthase inhibitor, L-(G)-nitro-L-arginine methyl ester (L-NAME). Concomitantly, NO levels, BH4 availability, and expression of DHFR were diminished under hypoxia. Application of folic acid (FA) restored DHFR levels, NO bioavailability, and BH4 levels under hypoxia. Importantly, FA prevented the development of hypoxia-induced PVR, right ventricular pressure increase, and RVH.
  
  
  METHODS
  FA-induced upregulation of DHFR recouples eNOS under hypoxia by improving BH4 recycling, thus preventing hypoxia-induced PH.
  
  
  CONCLUSIONS
  FA might serve as a novel therapeutic option combating PH.
authors.affiliation: 1 Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the Technical University Munich , Munich, Germany .
authors.forename: Karel
authors.initials: K
authors.lastname: Chalupsky
authors.affiliation: 1 Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the Technical University Munich , Munich, Germany .
authors.forename: Damir
authors.initials: D
authors.lastname: Kračun
authors.affiliation: 1 Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the Technical University Munich , Munich, Germany .
authors.forename: Ivan
authors.initials: I
authors.lastname: Kanchev
authors.affiliation: 1 Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the Technical University Munich , Munich, Germany .
authors.forename: Katharina
authors.initials: K
authors.lastname: Bertram
authors.affiliation: 1 Experimental and Molecular Pediatric Cardiology, German Heart Center Munich at the Technical University Munich , Munich, Germany .|2 DZHK (German Centre for Cardiovascular Research) , Partner Site Munich Heart Alliance, Munich, Germany .
authors.forename: Agnes
authors.initials: A
authors.lastname: Görlach
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000473:pathology; D005492:Folic Acid / Q000494:pharmacology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology*; D017380:Hypertrophy, Right Ventricular / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011651:Pulmonary Artery / Q000473:pathology; D013481:Superoxides / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D066253:Vascular Remodeling; D017725:Ventricular Pressure
chemical_list: D002316:Cardiotonic Agents; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D005492:Folic Acid; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D013762:Tetrahydrofolate Dehydrogenase; C003402:sapropterin