title: Contractile Function During Angiotensin-II Activation: Increased Nox2 Activity Modulates Cardiac Calcium Handling via Phospholamban Phosphorylation.
abstract: BACKGROUND
  Renin-angiotensin system activation is a feature of many cardiovascular conditions. Activity of myocardial reduced nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2 or Nox2) is enhanced by angiotensin II (Ang II) and contributes to increased hypertrophy, fibrosis, and adverse remodeling. Recent studies found that Nox2-mediated reactive oxygen species production modulates physiological cardiomyocyte function.
  
  
  OBJECTIVE
  This study sought to investigate the effects of cardiomyocyte Nox2 on contractile function during increased Ang II activation.
  
  
  METHODS
  We generated a cardiomyocyte-targeted Nox2-transgenic mouse model and studied the effects of in vivo and ex vivo Ang II stimulation, as well as chronic aortic banding.
  
  
  RESULTS
  Chronic subpressor Ang II infusion induced greater cardiac hypertrophy in transgenic than wild-type mice but unexpectedly enhanced contractile function. Acute Ang II treatment also enhanced contractile function in transgenic hearts in vivo and transgenic cardiomyocytes ex vivo. Ang II-stimulated Nox2 activity increased sarcoplasmic reticulum (SR) Ca(2+) uptake in transgenic mice, increased the Ca(2+) transient and contractile amplitude, and accelerated cardiomyocyte contraction and relaxation. Elevated Nox2 activity increased phospholamban phosphorylation in both hearts and cardiomyocytes, related to inhibition of protein phosphatase 1 activity. In a model of aortic banding-induced chronic pressure overload, heart function was similarly depressed in transgenic and wild-type mice.
  
  
  CONCLUSIONS
  We identified a novel mechanism in which Nox2 modulates cardiomyocyte SR Ca(2+) uptake and contractile function through redox-regulated changes in phospholamban phosphorylation. This mechanism can drive increased contractility in the short term in disease states characterized by enhanced renin-angiotensin system activation.
authors.affiliation: King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Prosser
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Moradeke A
authors.initials: MA
authors.lastname: Bamboye
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Education, Campus XII, University of Bahia State, Guanambi, Brazil.
authors.forename: Antonio N S
authors.initials: ANS
authors.lastname: Gondim
authors.affiliation: King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Celio X
authors.initials: CX
authors.lastname: Santos
authors.affiliation: King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ghigo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.affiliation: King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
authors.forename: Alison C
authors.initials: AC
authors.lastname: Brewer
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ward
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: W Jonathan
authors.initials: WJ
authors.lastname: Lederer
authors.affiliation: King's College London British Heart Foundation Centre of Excellence, London, United Kingdom. Electronic address: ajay.shah@kcl.ac.uk.
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000378:metabolism*; D004195:Disease Models, Animal; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D000804:Angiotensin II; D002118:Calcium; D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D000099211:Phospholamban; C488842:Cybb protein, mouse
keywords: NADPH oxidase; angiotensin II; contraction; myocyte