Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ.
The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect.
Vergeade
Aurélia
A
INSERM U644, University of Rouen, Rouen F-76183, France.
Mulder
Paul
P
Vendeville-Dehaudt
Cathy
C
Estour
François
F
Fortin
Dominique
D
Ventura-Clapier
Renée
R
Thuillez
Christian
C
Monteil
Christelle
C
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D003042:Cocaine; D019970:Cocaine-Related Disorders / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D004198:Disease Susceptibility; D004353:Drug Evaluation, Preclinical; D006331:Heart Diseases / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000150:complications* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D010101:Oxygen Consumption / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000975:Antioxidants; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C429014:mitoquinone; D003042:Cocaine