Published online before print June 21, 2007, doi: 10.1161/CIRCRESAHA.107.148015
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Submitted on January 8, 2007
Revised on April 30, 2007
Accepted on June 8, 2007
Hypoxia-Dependent Regulation of Nonphagocytic NADPH Oxidase Subunit NOX4 in the Pulmonary Vasculature
Manish Mittal ;
From the University of Giessen Lung Center (M.M., M.R., S.H., E.D., P.G., A.-C.S., R.T.S., H.A.G., J.H., S.W., F.G., N.W.), Medical Clinic II/V, the Department of Anatomy and Cell Biology (P.K., W.K.), and the Department of Pathology (G.K., L.F.), Justus-Liebig-University, Giessen, Germany; the Department of Cardiothoracic Surgery (W.K., M.A.R.H.), University of Vienna, Austria; and the Department of Pharmacology (H.H.H.W.S.), Monash University, Melbourne, Australia. Present address for P.K.: Institut für Anatomie, Universität zu Lübeck, Germany.
* To whom correspondence should be addressed. E-mail: Norbert.Weissmann{at}uglc.de.
Nonphagocytic NADPH oxidases have recently been suggested to play a major role in the regulation of physiological and pathophysiological processes, in particular, hypertrophy, remodeling, and angiogenesis in the systemic circulation. Moreover, NADPH oxidases have been suggested to serve as oxygen sensors in the lung. Chronic hypoxia induces vascular remodeling with medial hypertrophy leading to the development of pulmonary hypertension. We screened lung tissue for the expression of NADPH oxidase subunits. NOX1, NOXA1, NOXO1, p22phox, p47phox, p40phox, p67phox, NOX2, and NOX4 were present in mouse lung tissue. Comparing mice maintained for 21 days under hypoxic (10% O2) or normoxic (21% O2) conditions, an upregulation exclusively of NOX4 mRNA was observed under hypoxia in homogenized lung tissue, concomitant with increased levels in microdissected pulmonary arterial vessels. In situ hybridization and immunohistological staining for NOX4 in mouse lungs revealed a localization of NOX4 mRNA and protein predominantly in the media of small pulmonary arteries, with increased labeling intensities after chronic exposure to hypoxia. In isolated pulmonary arterial smooth muscle cells (PASMCs), NOX4 was localized primarily to the perinuclear space and its expression levels were increased after exposure to hypoxia. Treatment of PASMCs with siRNA directed against NOX4 decreased NOX4 mRNA levels and reduced PASMC proliferation as well as generation of reactive oxygen species. In lungs from patients with idiopathic pulmonary arterial hypertension (IPAH), expression levels of NOX4, which was localized in PASMCs, were 2.5-fold upregulated. These results support an important role for NOX4 in the vascular remodeling associated with development of pulmonary hypertension.
Key words: hypoxia • hypoxic pulmonary vasoconstriction • NADPH oxidase • pulmonary hypertension • vascular smooth muscle cell proliferation
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