Compensated volume overload increases the vulnerability of heart mitochondria without affecting their functions in the absence of stress

Although mitochondrial dysfunction has often been associated to heart failure, it has been suggested that it may represent only a late phenomenon in the disease process. We hypothesized that mitochondrial vulnerability to stress could be impaired in hypertrophied but non-decompensated hearts at a ti...

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Bibliographic Details
Published in:Journal of molecular and cellular cardiology 2006-12, Vol.41 (6), p.998-1009
Main Authors: Marcil, Mariannick, Ascah, Alexis, Matas, Jimmy, Bélanger, Sonia, Deschepper, Christian F., Burelle, Yan
Format: Article
Language:English
Subjects:
Animals
Calcium - metabolism
Electron Transport
Heart failure
Heart Failure - etiology
Heart Failure - metabolism
Hypertrophy
Hypoxia/anoxia
In Vitro Techniques
Male
Membrane Potential, Mitochondrial
Mitochondria
Mitochondria, Heart - metabolism
Mitochondrial Membrane Transport Proteins - metabolism
Myocardial Reperfusion Injury - metabolism
NAD - metabolism
Oxidative Phosphorylation
Rats
Rats, Inbred Strains
Ventricular Remodeling - physiology
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Summary:Although mitochondrial dysfunction has often been associated to heart failure, it has been suggested that it may represent only a late phenomenon in the disease process. We hypothesized that mitochondrial vulnerability to stress could be impaired in hypertrophied but non-decompensated hearts at a time when overt mitochondrial defects are not yet apparent. In the present study, hypertrophic remodeling was induced by means of an aorto-caval fistula (ACF) in WKHA rats and experiments were performed 12 weeks post surgery. At this time, ACF animals displayed normal contractile function, tissue oxidative capacity as well as mitochondrial membrane potential and respiratory function. However, compared to sham, mitochondria from ACF animals were more vulnerable to anoxia–reoxygenation injury in vitro as indicated by a greater impairment of oxidative phosphorylation and a greater dependence of respiration on exogenous NADH. Addition of the PTP inhibitor CsA restored respiratory function to the level observed in mitochondria from sham animals. Likewise, mitochondria from ACF displayed a greater sensitivity to Ca 2+-induced PTP opening in vitro compared to their sham counterparts. In addition to the greater vulnerability of mitochondria in vitro, mitochondrial PTP opening measured in situ in perfused hearts was greater following ischemia–reperfusion in ACF animals than in their sham counterparts. This was associated with a more impaired functional recovery and greater tissue damage during reperfusion in hearts from ACF vs sham. Taken together, these results indicate that, in response to volume overload, mitochondria may display increased vulnerability in the absence of any sign of dysfunction under baseline unstressed conditions, at a time when adverse ventricular remodelling is observed but systolic dysfunction and decompensation have not occurred yet.
ISSN:0022-2828
1095-8584
DOI:10.1016/j.yjmcc.2006.08.117