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Mitochondrial reactive oxygen species production and respiratory complex activity in rats with pressure overload‐induced heart failure
Author(s) -
Schwarzer Michael,
Osterholt Moritz,
Lunkenbein Anne,
Schrepper Andrea,
Amorim Paulo,
Doenst Torsten
Publication year - 2014
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2014.274704
Subject(s) - pressure overload , reactive oxygen species , heart failure , mitochondrial ros , medicine , muscle hypertrophy , mitochondrion , oxidative stress , cardiology , endocrinology , reactive nitrogen species , diastole , blood pressure , chemistry , biochemistry , cardiac hypertrophy
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.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.