|Silencing nox4 in the paraventricular nucleus improves myocardial infarction-induced cardiac dysfunction by attenuating sympathoexcitation and periinfarct apoptosis.|
|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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|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-04-22|
|Title: Circulation research Volume: 106 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2010 Jun|
|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|
|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.|
|APA/MLA Format Download EndNote Download BibTex|
Catalase / genetics, metabolism
Disease Models, Animal
Ganglionic Blockers / pharmacology
Gene Transfer Techniques
Genetic Therapy / methods
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*
Superoxide Dismutase / genetics, metabolism
Superoxides / metabolism
Sympathetic Nervous System / drug effects, metabolism, physiopathology*
Ventricular Function, Left
|HL63887/HL/NHLBI NIH HHS; HL84624/HL/NHLBI NIH HHS; R01 HL063887-09/HL/NHLBI NIH HHS; R01 HL084624-05/HL/NHLBI NIH HHS|
|0/Ganglionic Blockers; 11062-77-4/Superoxides; 51-41-2/Norepinephrine; 7722-84-1/Hydrogen Peroxide; EC 188.8.131.52/Catalase; EC 184.108.40.206/Superoxide Dismutase; EC 1.6.-/Nox4 protein, mouse; EC 220.127.116.11/NADPH Oxidase|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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