Heme oxygenase-2 and large-conductance Ca2+-activated K+ channels: lung vascular effects of hypoxia.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

MEASUREMENTS AND MAIN 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: Markus Roth, Markus Rupp, Simone Hofmann, Manish Mittal, Beate Fuchs, Natascha Sommer, Nirmal Parajuli, Karin Quanz, Dominic Schubert, Eva Dony, Ralph Theo Schermuly, Hossein Ardeschir Ghofrani, Ulrike Sausbier, Katrin Rutschmann, Sarah Wilhelm, Werner Seeger, Peter Ruth, Friedrich Grimminger, Matthias Sausbier, Norbert Weissmann
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 180 Issue 4 Pg. 353-64 (Aug 15 2009) ISSN: 1535-4970 [Electronic] United States
• PMID: 19498059 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
• RNA, Messenger
• Heme Oxygenase (Decyclizing)
• heme oxygenase-2

Topics

• Animals
• Heme Oxygenase (Decyclizing) (genetics, physiology)
• Hypertension, Pulmonary (pathology, physiopathology)
• Hypoxia (pathology, physiopathology)
• In Vitro Techniques
• Large-Conductance Calcium-Activated Potassium Channel alpha Subunits (genetics, physiology)
• Lung (blood supply, pathology)
• Mice
• Microscopy, Fluorescence
• Muscle, Smooth, Vascular (pathology, physiopathology)
• Polymerase Chain Reaction
• Pulmonary Alveoli (blood supply, pathology)
• Pulmonary Wedge Pressure (physiology)
• RNA, Messenger (genetics)
• Vasoconstriction (physiology)