title: Loss of p47phox subunit enhances susceptibility to biomechanical stress and heart failure because of dysregulation of cortactin and actin filaments.
abstract: BACKGROUND
  The classic phagocyte nicotinamide adenine dinucleotide phosphate oxidase (gp91(phox) or Nox2) is expressed in the heart. Nox2 activation requires membrane translocation of the p47(phox) subunit and is linked to heart failure. We hypothesized that loss of p47(phox) subunit will result in decreased reactive oxygen species production and resistance to heart failure.
  
  
  OBJECTIVE
  To define the role of p47(phox) in pressure overload-induced biomechanical stress.
  
  
  RESULTS
  Eight-week-old male p47(phox) null (p47(phox) knockout [KO]), Nox2 null (Nox2KO), and wild-type mice were subjected to transverse aortic constriction-induced pressure overload. Contrary to our hypothesis, p47(phox)KO mice showed markedly worsened systolic dysfunction in response to pressure overload at 5 and 9 weeks after transverse aortic constriction compared with wild-type-transverse aortic constriction mice. We found that biomechanical stress upregulated N-cadherin and β-catenin in p47(phox)KO hearts but disrupted the actin filament cytoskeleton and reduced phosphorylation of focal adhesion kinase. p47(phox) interacts with cytosolic cortactin by coimmunoprecipitation and double immunofluorescence staining in murine and human hearts and translocated to the membrane on biomechanical stress where cortactin interacted with N-cadherin, resulting in adaptive cytoskeletal remodeling. However, p47(phox)KO hearts showed impaired interaction of cortactin with N-cadherin, resulting in loss of biomechanical stress-induced actin polymerization and cytoskeletal remodeling. In contrast, Nox2 does not interact with cortactin, and Nox2-deficient hearts were protected from pressure overload-induced adverse myocardial and intracellular cytoskeletal remodeling.
  
  
  CONCLUSIONS
  We showed a novel role of p47(phox) subunit beyond and independent of nicotinamide adenine dinucleotide phosphate oxidase activity as a regulator of cortactin and adaptive cytoskeletal remodeling, leading to a paradoxically enhanced susceptibility to biomechanical stress and heart failure.
authors.affiliation: Department of Medicine, Division of Cardiology, University of Alberta, Edmonton T6G 2S2, AB, Canada.
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.forename: Zuocheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Dong
authors.initials: D
authors.lastname: Fan
authors.forename: Pavel
authors.initials: P
authors.lastname: Zhabyeyev
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.forename: Subhash K
authors.initials: SK
authors.lastname: Das
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.forename: Jessica
authors.initials: J
authors.lastname: Desaulniers
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000818:Animals; D001696:Biomechanical Phenomena; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D051356:Cortactin / Q000378:metabolism*; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D040542:Mechanotransduction, Cellular; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency* / Q000235:genetics; D018384:Oxidative Stress; D010766:Phosphorylation; D058105:Polymerization; D017382:Reactive Oxygen Species / Q000378:metabolism; D013314:Stress, Mechanical; D013997:Time Factors; D020257:Ventricular Remodeling; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000199:Actins; C495267:CTNNB1 protein, mouse; D015820:Cadherins; C489083:Cdh2 protein, mouse; D051356:Cortactin; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D051176:beta Catenin; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse
keywords: actin cytoskeleton; cortactin; heart failure; mechanotransduction; p47phox; pressure overload; remodeling