title: Heme oxygenase-2 and large-conductance Ca2+-activated K+ channels: lung vascular effects of hypoxia.
abstract: BACKGROUND
  Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism by which pulmonary gas exchange is optimized by the adaptation of blood flow to alveolar ventilation. In chronic hypoxia, in addition to HPV a vascular remodeling process leads to pulmonary hypertension. A complex of heme oxygenase-2 (HO-2) and the BK channel has been suggested as a universal oxygen sensor system.
  
  
  OBJECTIVE
  We investigated whether this complex serves as an oxygen sensor for the vascular effects of alveolar hypoxia in the lung.
  
  
  METHODS
  The investigations were performed in chronically hypoxic mice, in isolated perfused and ventilated lungs, and on the cellular level, including HO-2- and BK-channel deficient mice.
  
  
  RESULTS
  Immunohistochemical analysis of mouse lungs identified HO-2 mainly in pulmonary arteries, the bronchial epithelium, and alveolar epithelial cells. BK channel alpha-subunit (BKalpha) immunoreactivity was found primarily in the bronchial and vascular smooth muscle layer. Immunofluorescence staining and coimmunoprecipitation suggested only a weak complexation of HO-2 and BKalpha in pulmonary arterial smooth muscle cells. The strength of acute and sustained HPV, determined in isolated perfused and ventilated lungs, was not different among wild-type, HO-2-deficient, and BKalpha-deficient mice. Exposure of mice to 3 weeks of chronic hypoxia resulted in a slight down-regulation of HO-2 and no alteration in BKalpha expression. The degree of pulmonary hypertension that developed, quantified on the basis of right ventricular pressure, right-heart hypertrophy, and the degree of muscularization of precapillary pulmonary arteries, was not different among wild-type, HO-2-deficient, and BKalpha-deficient mice.
  
  
  CONCLUSIONS
  It is demonstrated that neither deletion of HO-2 nor BK channels affect acute, sustained, and chronic vascular responses to alveolar hypoxia in the lung.
authors.affiliation: University of Giessen Lung Center, Excellence Cluster Cardio-Pulmonary System, Medical Clinic II/V, Klinikstr. 36, D-35392 Giessen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Roth
authors.forename: Markus
authors.initials: M
authors.lastname: Rupp
authors.forename: Simone
authors.initials: S
authors.lastname: Hofmann
authors.forename: Manish
authors.initials: M
authors.lastname: Mittal
authors.forename: Beate
authors.initials: B
authors.lastname: Fuchs
authors.forename: Natascha
authors.initials: N
authors.lastname: Sommer
authors.forename: Nirmal
authors.initials: N
authors.lastname: Parajuli
authors.forename: Karin
authors.initials: K
authors.lastname: Quanz
authors.forename: Dominic
authors.initials: D
authors.lastname: Schubert
authors.forename: Eva
authors.initials: E
authors.lastname: Dony
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sausbier
authors.forename: Katrin
authors.initials: K
authors.lastname: Rutschmann
authors.forename: Sarah
authors.initials: S
authors.lastname: Wilhelm
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Matthias
authors.initials: M
authors.lastname: Sausbier
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
mesh_terms: D000818:Animals; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics* / Q000502:physiology*; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008856:Microscopy, Fluorescence; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D011650:Pulmonary Alveoli / Q000098:blood supply* / Q000473:pathology; D011669:Pulmonary Wedge Pressure / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2