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SHR Neuro Cancer Cardio Lipid Metab Microb
Mittal, M; Roth, M; König, P; Hofmann, S; Dony, E; Goyal, P; Selbitz, AC; Schermuly, RT; Ghofrani, HA; Kwapiszewska, G; Kummer, W; Klepetko, W; Hoda, MA; Fink, L; Hänze, J; Seeger, W; Grimminger, F; Schmidt, HH; Weissmann, N.
Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature.
Circ Res. 2007; 101(3): 258-267.
Doi: 10.1161/CIRCRESAHA.107.148015
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- Co-authors Med Uni Graz
- Kwapiszewska-Marsh Grazyna
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- Abstract:
- 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% O(2)) or normoxic (21% O(2)) 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 the vessel media, were 2.5-fold upregulated. These results support an important role for NOX4 in the vascular remodeling associated with development of pulmonary hypertension.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Anoxia - complications Anoxia - enzymology Anoxia - physiopathology
- Cell Division -
- Cells, Cultured - drug effects Cells, Cultured - enzymology
- Chronic Disease -
- Drug Design -
- Endoplasmic Reticulum - enzymology
- Enzyme Induction -
- Female -
- Humans -
- Hypertension, Pulmonary - drug therapy Hypertension, Pulmonary - enzymology Hypertension, Pulmonary - etiology Hypertension, Pulmonary - physiopathology
- Hypertrophy -
- Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
- Lung - blood supply
- Male -
- Membrane Glycoproteins - analysis
- Myocytes, Smooth Muscle - enzymology Myocytes, Smooth Muscle - pathology
- NADPH Oxidase - analysis NADPH Oxidase - biosynthesis NADPH Oxidase - genetics NADPH Oxidase - physiology
- Nitric Oxide - physiology
- Organ Specificity -
- Oxygen - metabolism Oxygen - pharmacology
- Protein Subunits -
- Pulmonary Artery - cytology Pulmonary Artery - enzymology
- RNA Interference -
- RNA, Messenger - biosynthesis
- RNA, Small Interfering - pharmacology
- Superoxides - metabolism
- Transforming Growth Factor beta1 - physiology
- Tunica Media - enzymology Tunica Media - pathology
- Find related publications in this database (Keywords)
- hypoxia
- hypoxic pulmonary vasoconstriction
- NADPH oxidase
- pulmonary hypertension
- vascular smooth muscle cell proliferation