Mitochondrial reactive oxygen species production and respiratory complex activity in rats with pressure overload‐induced heart failure

• Published in: The Journal of physiology 2014-09, Vol.592 (17), p.3767-3782
• Main Authors: Schwarzer, Michael, Osterholt, Moritz, Lunkenbein, Anne, Schrepper, Andrea, Amorim, Paulo, Doenst, Torsten
• Format: Article
• Language: English
• Subjects: 2,4-Dinitrophenol - pharmacology; 2,4-Dinitrophenol - therapeutic use; Animals; Cardiovascular; Cyclic N-Oxides - pharmacology; Cyclic N-Oxides - therapeutic use; Electron Transport Complex I - metabolism; Electron Transport Complex III - metabolism; Heart Failure - metabolism; Heart Failure - physiopathology; Heart Failure - prevention & control; Male; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Myocardial Contraction; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Uncoupling Agents - pharmacology; Uncoupling Agents - therapeutic use
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2014.274704

Key points Pressure overload induces cardiac hypertrophy developing into heart failure. During pressure overload‐induced heart failure development in the rat, mitochondrial capacity to produce reactive oxygen species (ROS) increased significantly with the onset of diastolic functional changes. Treatment to reduce ROS production was able to diminish mitochondrial ROS production but was not able to prevent or delay heart failure development. The results question a primary role of ROS in the mechanism causing contractile dysfunction under pressure overload. 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.