Mild hypothermia reduces per-ischemic reactive oxygen species production and preserves mitochondrial respiratory complexes.
BACKGROUND
Mitochondrial dysfunction is critical following ischemic disorders. Our goal was to determine whether mild hypothermia could limit this dysfunction through per-ischemic inhibition of reactive oxygen species (ROS) generation.


METHODS
First, ROS production was evaluated during simulated ischemia in an vitro model of isolated rat cardiomyocytes at hypothermic (32°C) vs. normothermic (38°C) temperatures. Second, we deciphered the direct effect of hypothermia on mitochondrial respiration and ROS production in oxygenated mitochondria isolated from rabbit hearts. Third, we investigated these parameters in cardiac mitochondria extracted after 30-min of coronary artery occlusion (CAO) under normothermic conditions (CAO-N) or with hypothermia induced by liquid ventilation (CAO-H; target temperature: 32°C).


RESULTS
In isolated rat cardiomyocytes, per-ischemic ROS generation was dramatically decreased at 32 vs. 38°C (e.g., -55±8% after 140min of hypoxia). In oxygenated mitochondria isolated from intact rabbit hearts, hypothermia also improved respiratory control ratio (+22±3%) and reduced H2O2 production (-41±1%). Decreased oxidative stress was further observed in rabbit hearts submitted to hypothermic vs. normothermic ischemia (CAO-H vs. CAO-N), using thiobarbituric acid-reactive substances as a marker. This was accompanied by a preservation of the respiratory control ratio as well as the activity of complexes I, II and III in cardiac mitochondria.


CONCLUSIONS
The cardioprotective effect of mild hypothermia involves a direct effect on per-ischemic ROS generation and results in preservation of mitochondrial function. This might explain why the benefit afforded by hypothermia during regional myocardial ischemia depends on how fast it is instituted during the ischemic process.
INSERM, U955, Equipe 3, Créteil, 94000, France. rtissier@vet-alfort.fr
Renaud
R
Tissier
Mourad
M
Chenoune
Sandrine
S
Pons
Roland
R
Zini
Lys
L
Darbera
Fanny
F
Lidouren
Bijan
B
Ghaleh
Alain
A
Berdeaux
Didier
D
Morin
D000818:Animals; D002478:Cells, Cultured; D007036:Hypothermia, Induced / Q000379:methods; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology*; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*
D017382:Reactive Oxygen Species