title: Right-ventricular failure is associated with increased mitochondrial complex II activity and production of reactive oxygen species.
abstract: OBJECTIVE
  Reactive oxygen species (ROS) have been implicated in the progression of ventricular hypertrophy to congestive heart failure. However, the source of increased oxidative stress in cardiomyocytes remains unclear.
  
  
  METHODS
  Here we examined NADPH oxidase and mitochondria as sources of ventricular ROS production in a rat model of right-ventricular (RV) failure (CHF) induced by pulmonary arterial hypertension (PAH).
  
  
  RESULTS
  Western analysis showed increased expression of the catalytic subunit gp91(phox) of NADPH oxidase as well as its activator Rac1 in RV in CHF compared to non-failing myocardium (CON). In addition, analysis of mitochondrial respiratory chain complexes showed a selective increase in the expression of Complex II subunit B. Using lucigenin chemiluminescence, tissue homogenates showed increased NADPH oxidase and Complex II-dependent ROS production in failing RV, with no increase in the left ventricle. Functional analyses of isolated RV mitochondria showed an increase in Complex II activity as well as Complex II-associated ROS production in CHF vs CON. An increase in the reduction state of the mitochondrial Coenzyme Q in failing RV, together with increased expression of hypoxia-inducible factor 1 alpha, indicated conditions in CHF that strongly favor ROS production by mitochondria. Reduced ROS-scavenging capacity was indicated by decreased mRNA levels of superoxide dismutases. Oxidative stress in failing RV was indicated by a two-fold increase in the level of phospho-p38 mitogen-activated protein kinase and by immunohistochemical evidence of extensive protein nitration.
  
  
  CONCLUSIONS
  These data show that the development of PAH-induced RV heart failure is associated with an increased capacity for ROS production by NADPH oxidase as well as mitochondria. The selective increase in expression and activity of mitochondrial Complex II may be particularly important for ventricular ROS production in heart failure.
authors.affiliation: Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Everaldo M
authors.initials: EM
authors.lastname: Redout
authors.forename: Marijke J
authors.initials: MJ
authors.lastname: Wagner
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Zuidwijk
authors.forename: Christa
authors.initials: C
authors.lastname: Boer
authors.forename: René J P
authors.initials: RJ
authors.lastname: Musters
authors.forename: Cornelis
authors.initials: C
authors.lastname: van Hardeveld
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
authors.forename: Warner S
authors.initials: WS
authors.lastname: Simonides
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001696:Biomechanical Phenomena; D042963:Electron Transport Complex II / Q000378:metabolism*; D006352:Heart Ventricles; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000378:metabolism; D049449:Luminescence; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D008856:Microscopy, Fluorescence; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D016686:Monocrotaline; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000032:analysis / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014451:Ubiquinone / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000378:metabolism* / Q000473:pathology; D020830:rac1 GTP-Binding Protein / Q000032:analysis
chemical_list: D015415:Biomarkers; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C478189:respiratory complex II; D014451:Ubiquinone; D016686:Monocrotaline; D042963:Electron Transport Complex II; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein