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Heme Oxygenase-2 and Large-Conductance Ca²⁺-activated K⁺ Channels

Lung Vascular Effects of Hypoxia

¹ University of Giessen Lung Center, Excellence Cluster Cardio-Pulmonary System, Medical Clinic II/V, Giessen, Germany; ² Pharmakologie und Toxikologie, Pharmazeutisches Institut, Universität Tübingen, Tübingen, Germany; and ³ Dualsystems Biotech AG, Schlieren, Switzerland

Correspondence and requests for reprints should be addressed to Norbert Weissmann, Ph.D., University of Giessen Lung Center, ECCPS, Medical Clinic II/V, Klinikstr. 36, D-35392 Giessen, Germany. E-mail: Norbert.Weissmann{at}uglc.de

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 -subunit (BK) 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 BK 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 BK-deficient mice. Exposure of mice to 3 weeks of chronic hypoxia resulted in a slight down-regulation of HO-2 and no alteration in BK 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 BK-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.

Key Words: oxygen sensor • hypoxic pulmonary vasoconstriction • vascular remodeling

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject A complex of heme oxygenase-2 (HO-2) and BK channels acts as an oxygen sensor in carotid body cells. It has been suggested that such a complex may be a universal oxygen sensor for other oxygen-sensing processes as well. What This Study Adds to the Field Murine HO-2 and BK channels are not involved in the acute, sustained, and chronic oxygen sensing underlying the pulmonary vascular response to alveolar hypoxia.