RGD Reference Report - The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice. - Rat Genome Database

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The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice.

Authors: Nisbet, RE  Graves, AS  Kleinhenz, DJ  Rupnow, HL  Reed, AL  Fan, TH  Mitchell, PO  Sutliff, RL  Hart, CM 
Citation: Nisbet RE, etal., Am J Respir Cell Mol Biol. 2009 May;40(5):601-9. Epub 2008 Oct 23.
RGD ID: 4762683
Pubmed: PMID:18952568   (View Abstract at PubMed)
PMCID: PMC2677439   (View Article at PubMed Central)
DOI: DOI:10.1165/2008-0145OC   (Journal Full-text)

Obstructive sleep apnea, characterized by intermittent periods of hypoxemia, is an independent risk factor for the development of pulmonary hypertension. However, the exact mechanisms of this disorder remain to be defined. Enhanced NADPH oxidase expression and superoxide (O2(-).) generation in the pulmonary vasculature play a critical role in hypoxia-induced pulmonary hypertension. Therefore, the current study explores the hypothesis that chronic intermittent hypoxia (CIH) causes pulmonary hypertension, in part, by increasing NADPH oxidase-derived reactive oxygen species (ROS) that contribute to pulmonary vascular remodeling and hypertension. To test this hypothesis, male C57Bl/6 mice and gp91phox knockout mice were exposed to CIH for 8 hours per day, 5 days per week for 8 weeks. CIH mice were placed in a chamber where the oxygen concentration was cycled between 21% and 10% O2 45 times per hour. Exposure to CIH for 8 weeks increased right ventricular systolic pressure (RVSP), right ventricle (RV):left ventricle (LV) + septum (S) weight ratio, an index of RV hypertrophy, and thickness of the right ventricular anterior wall as measured by echocardiography. CIH exposure also caused pulmonary vascular remodeling as demonstrated by increased muscularization of the distal pulmonary vasculature. CIH-induced pulmonary hypertension was associated with increased lung levels of the NADPH oxidase subunits, Nox4 and p22phox, as well as increased activity of platelet-derived growth factor receptor beta and its associated downstream effector, Akt kinase. These CIH-induced derangements were attenuated in similarly treated gp91phox knockout mice. These findings demonstrate that NADPH oxidase-derived ROS contribute to the development of pulmonary vascular remodeling and hypertension caused by CIH.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pulmonary hypertension  ISOCyba (Mus musculus)4762683; 4762683associated with Anoxia more ...RGD 
pulmonary hypertension  ISOCybb (Mus musculus)4762683; 4762683associated with AnoxiaRGD 
pulmonary hypertension  IEP 4762683; 4762683associated with Anoxia more ...RGD 
pulmonary hypertension  IMP 4762683associated with AnoxiaRGD 
pulmonary hypertension  ISONox4 (Mus musculus)4762683; 4762683associated with Anoxia more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyba  (cytochrome b-245 alpha chain)
Cybb  (cytochrome b-245 beta chain)
Nox4  (NADPH oxidase 4)

Genes (Mus musculus)
Cyba  (cytochrome b-245, alpha polypeptide)
Cybb  (cytochrome b-245, beta polypeptide)
Nox4  (NADPH oxidase 4)

Genes (Homo sapiens)
CYBA  (cytochrome b-245 alpha chain)
CYBB  (cytochrome b-245 beta chain)
NOX4  (NADPH oxidase 4)


Additional Information