title: Monoamine oxidase A-mediated enhanced catabolism of norepinephrine contributes to adverse remodeling and pump failure in hearts with pressure overload.
abstract: BACKGROUND
  Monoamine oxidases (MAOs) are mitochondrial enzymes that catabolize prohypertrophic neurotransmitters, such as norepinephrine and serotonin, generating hydrogen peroxide. Because excess reactive oxygen species and catecholamines are major contributors to the pathophysiology of congestive heart failure, MAOs could play an important role in this process.
  
  
  OBJECTIVE
  Here, we investigated the role of MAO-A in maladaptive hypertrophy and heart failure.
  
  
  RESULTS
  We report that MAO-A activity is triggered in isolated neonatal and adult myocytes on stimulation with norepinephrine, followed by increase in cell size, reactive oxygen species production, and signs of maladaptive hypertrophy. All of these in vitro changes occur, in part, independently from alpha- and beta-adrenergic receptor-operated signaling and are inhibited by the specific MAO-A inhibitor clorgyline. In mice with left ventricular dilation and pump failure attributable to pressure overload, norepinephrine catabolism by MAO-A is increased accompanied by exacerbated oxidative stress. MAO-A inhibition prevents these changes, and also reverses fetal gene reprogramming, metalloproteinase and caspase-3 activation, as well as myocardial apoptosis. The specific role of MAO-A was further tested in mice expressing a dominant-negative MAO-A (MAO-A(neo)), which were more protected against pressure overload than their wild-type littermates.
  
  
  CONCLUSIONS
  In addition to adrenergic receptor-dependent mechanisms, enhanced MAO-A activity coupled with increased intramyocardial norepinephrine availability results in augmented reactive oxygen species generation, contributing to maladaptive remodeling and left ventricular dysfunction in hearts subjected to chronic stress.
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Kaludercic
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagayama
authors.forename: Ning
authors.initials: N
authors.lastname: Feng
authors.forename: Edwin W
authors.initials: EW
authors.lastname: Lai
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
authors.forename: Jean C
authors.initials: JC
authors.lastname: Shih
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Lisa
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
mesh_terms: D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics; D003010:Clorgyline / Q000494:pharmacology; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics; D006352:Heart Ventricles / Q000201:enzymology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000235:genetics; D020257:Ventricular Remodeling
chemical_list: D008996:Monoamine Oxidase Inhibitors; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase; D003010:Clorgyline; D009638:Norepinephrine