Document Detail

Silencing nox4 in the paraventricular nucleus improves myocardial infarction-induced cardiac dysfunction by attenuating sympathoexcitation and periinfarct apoptosis.
MedLine Citation:
PMID:  20413786     Owner:  NLM     Status:  MEDLINE    
RATIONALE: Myocardial infarction (MI)-induced heart failure is characterized by central nervous system-driven sympathoexcitation and deteriorating cardiac function. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity and is implicated in heart failure. Redox signaling in the PVN and other central nervous system sites is a primary mechanism of neuro-cardiovascular regulation, and excessive oxidant production by activation of NADPH oxidases (Noxs) is implicated in some neuro-cardiovascular diseases.
OBJECTIVE: We tested the hypothesis that Nox-mediated redox signaling in the PVN contributes to MI-induced sympathoexcitation and cardiac dysfunction in mice.
METHODS AND RESULTS: Real-time PCR revealed that Nox4 was the most abundantly expressed Nox in PVN under basal conditions. Coronary arterial ligation (MI) caused a selective upregulation of this homolog compared to Nox1 and Nox2. Adenoviral gene transfer of Nox4 (AdsiNox4) to PVN (bilateral) attenuated MI-induced superoxide formation in this brain region (day 14) to the same level as that produced by PVN-targeted gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD). MI mice treated with AdsiNox4 or AdCu/ZnSOD in the PVN showed marked improvement in cardiac function as assessed by echocardiography and left ventricular hemodynamic analysis. This was accompanied by significantly diminished sympathetic outflow and apoptosis in the periinfarct region of the heart.
CONCLUSIONS: These results suggest that MI causes dysregulation of Nox4-mediated redox signaling in the PVN, which leads to sympathetic overactivation and a decline in cardiac function. Targeted inhibition of oxidant signaling in the PVN could provide a novel treatment for MI-induced heart failure.
David W Infanger; Xian Cao; Scott D Butler; Melissa A Burmeister; Yi Zhou; John A Stupinski; Ram V Sharma; Robin L Davisson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-04-22
Journal Detail:
Title:  Circulation research     Volume:  106     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-11     Completed Date:  2010-07-09     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1763-74     Citation Subset:  IM    
Professor of Molecular Physiology, Biomedical Sciences and Cell and Developmental Biology, Cornell University, T9-014 Veterinary Research Tower, Ithaca, NY 14853-6401, USA.
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MeSH Terms
Adenoviridae / genetics
Catalase / genetics,  metabolism
Disease Models, Animal
Ganglionic Blockers / pharmacology
Gene Silencing*
Gene Transfer Techniques
Genetic Therapy / methods
Genetic Vectors
Heart / innervation*
Heart Failure / enzymology*,  genetics,  pathology,  physiopathology,  prevention & control
Hydrogen Peroxide / metabolism
Mice, Inbred C57BL
Myocardial Infarction / enzymology*,  genetics,  pathology,  physiopathology,  therapy
Myocardium / pathology*
NADPH Oxidase / genetics,  metabolism*
Norepinephrine / urine
Paraventricular Hypothalamic Nucleus / enzymology*
RNA Interference
Signal Transduction
Superoxide Dismutase / genetics,  metabolism
Superoxides / metabolism
Sympathetic Nervous System / drug effects,  metabolism,  physiopathology*
Time Factors
Ventricular Function, Left
Grant Support
Reg. No./Substance:
0/Ganglionic Blockers; 11062-77-4/Superoxides; 51-41-2/Norepinephrine; 7722-84-1/Hydrogen Peroxide; EC; EC Dismutase; EC 1.6.-/Nox4 protein, mouse; EC Oxidase

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