title: Mitochondrial reactive oxygen species production and respiratory complex activity in rats with pressure overload-induced heart failure.
abstract: We investigated the impact of cardiac reactive oxygen species (ROS) during the development of pressure overload-induced heart failure. We used our previously described rat model where transverse aortic constriction (TAC) induces compensated hypertrophy after 2 weeks, heart failure with preserved ejection fraction at 6 and 10 weeks, and heart failure with systolic dysfunction after 20 weeks. We measured mitochondrial ROS production rates, ROS damage and assessed the therapeutic potential of in vivo antioxidant therapies. In compensated hypertrophy (2 weeks of TAC) ROS production rates were normal at both mitochondrial ROS production sites (complexes I and III). Complex I ROS production rates increased with the appearance of diastolic dysfunction (6 weeks of TAC) and remained high thereafter. Surprisingly, maximal ROS production at complex III peaked at 6 weeks of pressure overload. Mitochondrial respiratory capacity (state 3 respiration) was elevated 2 and 6 weeks after TAC, decreased after this point and was significantly impaired at 20 weeks, when contractile function was also impaired and ROS damage was found with increased hydroxynonenal. Treatment with the ROS scavenger α-phenyl-N-tert-butyl nitrone or the uncoupling agent dinitrophenol significantly reduced ROS production rates at 6 weeks. Despite the decline in ROS production capacity, no differences in contractile function between treated and untreated animals were observed. Increased ROS production occurs early in the development of heart failure with a peak at the onset of diastolic dysfunction. However, ROS production may not be related to the onset of contractile dysfunction.
authors.affiliation: Department of Cardiothoracic Surgery, Jena University Hospital Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarzer
authors.affiliation: Department of Cardiothoracic Surgery, Jena University Hospital Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Osterholt
authors.affiliation: Department of Cardiac Surgery, University of Leipzig Heart Center, Leipzig, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Lunkenbein
authors.affiliation: Department of Cardiothoracic Surgery, Jena University Hospital Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schrepper
authors.affiliation: Department of Cardiothoracic Surgery, Jena University Hospital Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Paulo
authors.initials: P
authors.lastname: Amorim
authors.affiliation: Department of Cardiothoracic Surgery, Jena University Hospital Friedrich Schiller University of Jena, Jena, Germany doenst@med.uni-jena.de.
authors.forename: Torsten
authors.initials: T
authors.lastname: Doenst
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use; D042967:Electron Transport Complex I / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009200:Myocardial Contraction; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; C029217:phenyl-N-tert-butylnitrone; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D019297:2,4-Dinitrophenol