title: Monoamine oxidase B prompts mitochondrial and cardiac dysfunction in pressure overloaded hearts.
abstract: OBJECTIVE
  Monoamine oxidases (MAOs) are mitochondrial flavoenzymes responsible for neurotransmitter and biogenic amines catabolism. MAO-A contributes to heart failure progression via enhanced norepinephrine catabolism and oxidative stress. The potential pathogenetic role of the isoenzyme MAO-B in cardiac diseases is currently unknown. Moreover, it is has not been determined yet whether MAO activation can directly affect mitochondrial function.
  
  
  RESULTS
  In wild type mice, pressure overload induced by transverse aortic constriction (TAC) resulted in enhanced dopamine catabolism, left ventricular (LV) remodeling, and dysfunction. Conversely, mice lacking MAO-B (MAO-B(-/-)) subjected to TAC maintained concentric hypertrophy accompanied by extracellular signal regulated kinase (ERK)1/2 activation, and preserved LV function, both at early (3 weeks) and late stages (9 weeks). Enhanced MAO activation triggered oxidative stress, and dropped mitochondrial membrane potential in the presence of ATP synthase inhibitor oligomycin both in neonatal and adult cardiomyocytes. The MAO-B inhibitor pargyline completely offset this change, suggesting that MAO activation induces a latent mitochondrial dysfunction, causing these organelles to hydrolyze ATP. Moreover, MAO-dependent aldehyde formation due to inhibition of aldehyde dehydrogenase 2 activity also contributed to alter mitochondrial bioenergetics.
  
  
  METHODS
  Our study unravels a novel role for MAO-B in the pathogenesis of heart failure, showing that both MAO-driven reactive oxygen species production and impaired aldehyde metabolism affect mitochondrial function.
  
  
  CONCLUSIONS
  Under conditions of chronic hemodynamic stress, enhanced MAO-B activity is a major determinant of cardiac structural and functional disarrangement. Both increased oxidative stress and the accumulation of aldehyde intermediates are likely liable for these adverse morphological and mechanical changes by directly targeting mitochondria.
authors.affiliation: 1 Neuroscience Institute , National Research Council of Italy, Padova, Italy .
authors.forename: Nina
authors.initials: N
authors.lastname: Kaludercic
authors.forename: Andrea
authors.initials: A
authors.lastname: Carpi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagayama
authors.forename: Vidhya
authors.initials: V
authors.lastname: Sivakumaran
authors.forename: Guangshuo
authors.initials: G
authors.lastname: Zhu
authors.forename: Edwin W
authors.initials: EW
authors.lastname: Lai
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Agnese
authors.initials: A
authors.lastname: De Mario
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Merry L
authors.initials: ML
authors.lastname: Lindsey
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: Jean C
authors.initials: JC
authors.lastname: Shih
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: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001794:Blood Pressure; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D004789:Enzyme Activation; D005355:Fibrosis; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D016277:Ventricular Function, Left
chemical_list: D000447:Aldehydes; D017382:Reactive Oxygen Species; D008995:Monoamine Oxidase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D004298:Dopamine