Document Detail


Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature.
MedLine Citation:
PMID:  17585072     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Manish Mittal; Markus Roth; Peter König; Simone Hofmann; Eva Dony; Parag Goyal; Anne-Christin Selbitz; Ralph Theo Schermuly; Hossein Ardeschir Ghofrani; Grazyna Kwapiszewska; Wolfgang Kummer; Walter Klepetko; Mir Ali Reza Hoda; Ludger Fink; Jörg Hänze; Werner Seeger; Friedrich Grimminger; Harald H H W Schmidt; Norbert Weissmann
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-06-21
Journal Detail:
Title:  Circulation research     Volume:  101     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2007 Aug 
Date Detail:
Created Date:  2007-08-03     Completed Date:  2007-09-14     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  258-67     Citation Subset:  IM    
Affiliation:
University of Giessen Lung Center, Medical Clinic II/V, Giessen, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anoxia / complications,  enzymology*,  physiopathology
Cell Division
Cells, Cultured / drug effects,  enzymology
Chronic Disease
Drug Design
Endoplasmic Reticulum / enzymology
Enzyme Induction
Female
Humans
Hypertension, Pulmonary / drug therapy,  enzymology*,  etiology,  physiopathology
Hypertrophy
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Lung / blood supply
Male
Membrane Glycoproteins / analysis
Myocytes, Smooth Muscle / enzymology,  pathology
NADPH Oxidase / analysis,  biosynthesis,  genetics,  physiology*
Nitric Oxide / physiology
Organ Specificity
Oxygen / metabolism,  pharmacology
Protein Subunits
Pulmonary Artery / cytology,  enzymology
RNA Interference
RNA, Messenger / biosynthesis
RNA, Small Interfering / pharmacology
Superoxides / metabolism
Transforming Growth Factor beta1 / physiology
Tunica Media / enzymology,  pathology
Chemical
Reg. No./Substance:
0/CYBB protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Membrane Glycoproteins; 0/Protein Subunits; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Transforming Growth Factor beta1; 10102-43-9/Nitric Oxide; 11062-77-4/Superoxides; 7782-44-7/Oxygen; EC 1.6.-/Nox4 protein, mouse; EC 1.6.3.-/NOX4 protein, human; EC 1.6.3.1/Cybb protein, mouse; EC 1.6.3.1/NADPH Oxidase
Comments/Corrections
Comment In:
Circ Res. 2007 Aug 3;101(3):224-6   [PMID:  17673680 ]

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