Chronic hypoxia-induced alterations in mitochondrial energy metabolism are not reversible in rat heart ventricles

Nouette-Gaulain, Karine; Biais, Matthieu; Savineau, Jean-Pierre; Marthan, Roger; Mazat, Jean-Pierre; Letellier, Thierry; Sztark, François
January 2011
Canadian Journal of Physiology & Pharmacology;Jan2011, Vol. 89 Issue 1, p58
Academic Journal
Chronic hypoxia alters mitochondrial energy metabolism. In the heart, oxidative capacity of both ventricles is decreased after 3 weeks of chronic hypoxia. The aim of this study was to evaluate the reversal of these metabolic changes upon normoxia recovery. Rats were exposed to a hypobaric environment for 3 weeks and then subjected to a normoxic environment for 3 weeks (normoxia-recovery group) and compared with rats maintained in a normoxic environment (control group). Mitochondrial energy metabolism was differentially examined in both left and right ventricles. Oxidative capacity (oxygen consumption and ATP synthesis) was measured in saponin-skinned fibers. Activities of mitochondrial respiratory chain complexes and antioxidant enzymes were measured on ventricle homogenates. Morphometric analysis of mitochondria was performed on electron micrographs. In normoxia-recovery rats, oxidative capacities of right ventricles were decreased in the presence of glutamate or palmitoyl carnitine as substrates. In contrast, oxidation of palmitoyl carnitine was maintained in the left ventricle. Enzyme activities of complexes III and IV were significantly decreased in both ventricles. These functional alterations were associated with a decrease in numerical density and an increase in size of mitochondria. Finally, in the normoxia-recovery group, the antioxidant enzyme activities (catalase and glutathione peroxidase) increased. In conclusion, alterations of mitochondrial energy metabolism induced by chronic hypoxia are not totally reversible. Reactive oxygen species could be involved and should be investigated under such conditions, since they may represent a therapeutic target. L'hypoxie chronique modifie le métabolisme énergétique des mitochondries. Dans le cœur, la capacité oxydative des 2 ventricules diminue après 3 semaines d'hypoxie chronique. La présente étude a eu pour but d'évaluer la réversibilité des modifications métaboliques lors du retour en normoxie. On a exposé des rats à un environnement hypobare pendant 3 semaines, puis à un environnement normoxique pendant 3 semaines (groupe retour en normoxie), et on les a ensuite comparés avec des rats maintenus dans un environnement normoxique (groupe témoin). On a examiné le métabolisme énergétique des mitochondries dans les ventricules gauche et droit. On a mesuré la capacité oxydative (consommation d'oxygène et synthèse d'ATP) dans des fibres pelées à l'aide de saponine. On a mesuré les activités des complexes de la chaîne respiratoire mitochondriale et d'enzymes antioxydantes sur des homogénats de ventricules. On a effectué une analyse morphométrique des mitochondries en microscopie électronique. Chez les rats du groupe retour en normoxie, les capacités oxydatives du ventricule droit ont diminué lorsque le glutamate ou la palmitoyl carnitine ont été utilisés comme substrats. À l'opposé, l'oxydation de la palmitoyl carnitine a été maintenue dans le ventricule gauche. Les activités enzymatiques des complexes III et IV ont diminué de manière significative dans les 2 ventricules. Ces modifications fonctionnelles ont été associées à une diminution de la densité numérique et à une augmentation de la taille des mitochondries. Enfin, chez le groupe retour en normoxie, les activités des enzymes antioxydantes (catalase et glutathion peroxydase) ont augmenté. Ainsi, les modifications du métabolisme énergétique des mitochondries induites par l'hypoxie chronique ne sont pas totalement réversibles. Les ROS pourraient être en cause et devraient être examinés dans ces conditions puisqu'elles pourraient représenter une cible thérapeutique.


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