Document Detail

NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis.
MedLine Citation:
PMID:  20921387     Owner:  NLM     Status:  MEDLINE    
Cardiac failure occurs when the heart fails to adapt to chronic stresses. Reactive oxygen species (ROS)-dependent signaling is implicated in cardiac stress responses, but the role of different ROS sources remains unclear. Here we report that NADPH oxidase-4 (Nox4) facilitates cardiac adaptation to chronic stress. Unlike other Nox proteins, Nox4 activity is regulated mainly by its expression level, which increases in cardiomyocytes under stresses such as pressure overload or hypoxia. To investigate the functional role of Nox4 during the cardiac response to stress, we generated mice with a genetic deletion of Nox4 or a cardiomyocyte-targeted overexpression of Nox4. Basal cardiac function was normal in both models, but Nox4-null animals developed exaggerated contractile dysfunction, hypertrophy, and cardiac dilatation during exposure to chronic overload whereas Nox4-transgenic mice were protected. Investigation of mechanisms underlying this protective effect revealed a significant Nox4-dependent preservation of myocardial capillary density after pressure overload. Nox4 enhanced stress-induced activation of cardiomyocyte hypoxia inducible factor 1 and the release of vascular endothelial growth factor, resulting in increased paracrine angiogenic activity. These data indicate that cardiomyocyte Nox4 is a unique inducible regulator of myocardial angiogenesis, a key determinant of cardiac adaptation to overload stress. Our results also have wider relevance to the use of nonspecific antioxidant approaches in cardiac disease and may provide an explanation for the failure of such strategies in many settings.
Min Zhang; Alison C Brewer; Katrin Schröder; Celio X C Santos; David J Grieve; Minshu Wang; Narayana Anilkumar; Bin Yu; Xuebin Dong; Simon J Walker; Ralf P Brandes; Ajay M Shah
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-04
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-20     Completed Date:  2010-11-22     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18121-6     Citation Subset:  IM    
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MeSH Terms
Heart / physiopathology*
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Mice, Transgenic
Myocardium / metabolism
NADPH Oxidase / genetics,  metabolism*
Neovascularization, Physiologic*
Stress, Physiological*
Vascular Endothelial Growth Factor A / metabolism
Grant Support
CH/99001//British Heart Foundation; G0601215//Medical Research Council; PG/09/102/28133//British Heart Foundation; RE/08/003//British Heart Foundation; RG/08/011/25922//British Heart Foundation
Reg. No./Substance:
0/Hif1a protein, mouse; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Vascular Endothelial Growth Factor A; EC 1.6.-/Nox4 protein, mouse; EC Oxidase

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