title: Silencing nox4 in the paraventricular nucleus improves myocardial infarction-induced cardiac dysfunction by attenuating sympathoexcitation and periinfarct apoptosis.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Professor of Molecular Physiology, Biomedical Sciences and Cell and Developmental Biology, Cornell University, T9-014 Veterinary Research Tower, Ithaca, NY 14853-6401, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Infanger
authors.forename: Xian
authors.initials: X
authors.lastname: Cao
authors.forename: Scott D
authors.initials: SD
authors.lastname: Butler
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Burmeister
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: John A
authors.initials: JA
authors.lastname: Stupinski
authors.forename: Ram V
authors.initials: RV
authors.lastname: Sharma
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005730:Ganglionic Blockers / Q000494:pharmacology; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006321:Heart / Q000294:innervation*; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D006439:Hemodynamics; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000473:pathology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009638:Norepinephrine / Q000652:urine; D010084:Oxidation-Reduction; D010286:Paraventricular Hypothalamic Nucleus / Q000201:enzymology*; D034622:RNA Interference; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors; D016277:Ventricular Function, Left
chemical_list: D005730:Ganglionic Blockers; D013481:Superoxides; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D009638:Norepinephrine