title: Vulnerability of the developing heart to oxygen deprivation as a cause of congenital heart defects.
abstract: BACKGROUND
  The heart develops under reduced and varying oxygen concentrations, yet there is little understanding of oxygen metabolism in the normal and mal-development of the heart. Here we used a novel reagent, the ODD-Luc hypoxia reporter mouse (oxygen degradation domain, ODD) of Hif-1α fused to Luciferase (Luc), to assay the activity of the oxygen sensor, prolyl hydroxylase, and oxygen reserve, in the developing heart. We tested the role of hypoxia-dependent responses in heart development by targeted inactivation of Hif-1α.
  
  
  RESULTS
  ODD-Luciferase activity was 14-fold higher in mouse embryonic day 10.5 (E10.5) versus adult heart and liver tissue lysates. ODD-Luc activity decreased in 2 stages, the first corresponding with the formation of a functional cardiovascular system for oxygen delivery at E15.5, and the second after birth consistent with complete oxygenation of the blood and tissues. Reduction of maternal inspired oxygen to 8% for 4 hours caused minimal induction of luciferase activity in the maternal tissues but robust induction in the embryonic tissues in proportion to the basal activity, indicating a lack of oxygen reserve, and corresponding induction of a hypoxia-dependent gene program. Bioluminescent imaging of intact embryos demonstrated highest activity in the outflow portion of the E13.5 heart. Hif-1α inactivation or prolonged hypoxia caused outflow and septation defects only when targeted to this specific developmental window.
  
  
  CONCLUSIONS
  Low oxygen concentrations and lack of oxygen reserve during a critical phase of heart organogenesis may provide a basis for vulnerability to the development of common septation and conotruncal heart defects.
authors.affiliation: Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD (D.K., S.A.F.).
authors.forename: Doreswamy
authors.initials: D
authors.lastname: Kenchegowda
authors.affiliation: Department of Medicine (Cardiology), Case Western Reserve University, Cleveland, OH (H.L., L.L., S.A.F.).
authors.forename: Hongbin
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD (K.T., S.S.M., S.A.F.).
authors.forename: Keyata
authors.initials: K
authors.lastname: Thompson
authors.affiliation: Department of Medicine (Cardiology), Case Western Reserve University, Cleveland, OH (H.L., L.L., S.A.F.).
authors.forename: Liping
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD (K.T., S.S.M., S.A.F.).
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Martin
authors.affiliation: Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD (D.K., S.A.F.) Department of Physiology, University of Maryland School of Medicine, Baltimore, MD (K.T., S.S.M., S.A.F.) Department of Medicine (Cardiology), Case Western Reserve University, Cleveland, OH (H.L., L.L., S.A.F.).
authors.forename: Steven A
authors.initials: SA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000209:etiology* / Q000473:pathology; D000860:Hypoxia / Q000196:embryology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D010100:Oxygen / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008156:Luciferases; D010100:Oxygen
keywords: conotruncus; hypoxia; neural crest; persistent truncus arteriosus