Heme oxygenase-2 and large-conductance Ca2+-activated K+ channels: lung vascular effects of hypoxia.
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.
Roth
Markus
M
University of Giessen Lung Center, Excellence Cluster Cardio-Pulmonary System, Medical Clinic II/V, Klinikstr. 36, D-35392 Giessen, Germany.
Rupp
Markus
M
Hofmann
Simone
S
Mittal
Manish
M
Fuchs
Beate
B
Sommer
Natascha
N
Parajuli
Nirmal
N
Quanz
Karin
K
Schubert
Dominic
D
Dony
Eva
E
Schermuly
Ralph Theo
RT
Ghofrani
Hossein Ardeschir
HA
Sausbier
Ulrike
U
Rutschmann
Katrin
K
Wilhelm
Sarah
S
Seeger
Werner
W
Ruth
Peter
P
Grimminger
Friedrich
F
Sausbier
Matthias
M
Weissmann
Norbert
N
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*
D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2