Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH
Nina B Radford1, Bang Wan, Angela Richman
1The Cooper Clinic, Dallas, Texas 75230, USA.
Insights
Mice lacking Cytochrome-c oxidase subunit VIaH (COXVIaH) showed impaired cardiac diastolic function. This suggests COXVIaH is crucial for heart performance, even with normal ATP levels.
Area of Science:
- Biochemistry
- Cardiology
- Molecular Biology
Background:
- Cytochrome-c oxidase subunit VIaH (COXVIaH) is known to modulate Cytochrome-c oxidase (COX) activity.
- Its precise role in cardiac energy production and mechanical function requires further elucidation.
Purpose of the Study:
- To investigate the function of COXVIaH in regulating oxidative energy production and cardiac mechanical performance.
- To determine the impact of COXVIaH deficiency on myocardial function and energy metabolism.
Main Methods:
- Generation of gene-targeted mice lacking COXVIaH.
- Assessment of total COX activity and myocardial ATP levels in wild-type and mutant hearts.
- Evaluation of myocardial performance using isolated working heart preparations.
- Measurement of left ventricular end-diastolic volume via magnetic resonance imaging.
Main Results:
- Mutant mice exhibited decreased total COX activity in the heart, attributed to altered COX holoenzyme assembly.
- Despite reduced COX activity, myocardial ATP levels remained comparable between wild-type and mutant mice.
- Hearts from mutant mice demonstrated impaired stroke work generation at increased filling pressures.
- Magnetic resonance imaging indicated diastolic dysfunction, specifically impaired ventricular filling, in mutant mice.
Conclusions:
- Genetic deficiency of COXVIaH significantly impacts myocardial diastolic performance.
- COXVIaH plays a critical role in cardiac mechanical function, independent of cellular ATP levels.
- Altered COX holoenzyme assembly due to COXVIaH absence contributes to cardiac dysfunction.
Abstract:
Cytochrome-c oxidase subunit VIaH (COXVIaH) has been implicated in the modulation of COX activity. A gene-targeting strategy was undertaken to generate mice that lacked COXVIaH to determine its role in regulation of oxidative energy production and mechanical performance in cardiac muscle. Total COX activity was decreased in hearts from mutant mice, which appears to be a consequence of altered assembly of the holoenzyme COX. However, total myocardial ATP was not significantly different in wild-type and mutant mice. Myocardial performance was examined using the isolated working heart preparation. As left atrial filling pressure increased, hearts from mutant mice were unable to generate equivalent stroke work compared with hearts from wild-type mice. Direct measurement of left ventricular end-diastolic volume using magnetic resonance imaging revealed that cardiac dysfunction was a consequence of impaired ventricular filling or diastolic dysfunction. These findings suggest that a genetic deficiency of COXVIaH has a measurable impact on myocardial diastolic performance despite the presence of normal cellular ATP levels.
