title: Mild hypothermia attenuates mitochondrial oxidative stress by protecting respiratory enzymes and upregulating MnSOD in a pig model of cardiac arrest.
abstract: Mild hypothermia is the only effective treatment confirmed clinically to improve neurological outcomes for comatose patients with cardiac arrest. However, the underlying mechanism is not fully elucidated. In this study, our aim was to determine the effect of mild hypothermia on mitochondrial oxidative stress in the cerebral cortex. We intravascularly induced mild hypothermia (33°C), maintained this temperature for 12 h, and actively rewarmed in the inbred Chinese Wuzhishan minipigs successfully resuscitated after 8 min of untreated ventricular fibrillation. Cerebral samples were collected at 24 and 72 h following return of spontaneous circulation (ROSC). We found that mitochondrial malondialdehyde and protein carbonyl levels were significantly increased in the cerebral cortex in normothermic pigs even at 24 h after ROSC, whereas mild hypothermia attenuated this increase. Moreover, mild hypothermia attenuated the decrease in Complex I and Complex III (i.e., major sites of reactive oxygen species production) activities of the mitochondrial respiratory chain and increased antioxidant enzyme manganese superoxide dismutase (MnSOD) activity. This increase in MnSOD activity was consistent with the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and protein expressions, and with the increase of Nrf2 nuclear translocation in normothermic pigs at 24 and 72 h following ROSC, whereas mild hypothermia enhanced these tendencies. Thus, our findings indicate that mild hypothermia attenuates mitochondrial oxidative stress in the cerebral cortex, which may be associated with reduced impairment of mitochondrial respiratory chain enzymes, and enhancement of MnSOD activity and expression via Nrf2 activation.
authors.affiliation: Department of Emergency, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Hua
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Zi-Ren
authors.initials: ZR
authors.lastname: Tang
authors.forename: Xue
authors.initials: X
authors.lastname: Mei
authors.forename: Ming-Yue
authors.initials: MY
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Cui
mesh_terms: D000818:Animals; D005260:Female; D006323:Heart Arrest / Q000378:metabolism* / Q000628:therapy; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D050050:Protein Carbonylation / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D013552:Swine; D013556:Swine, Miniature; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D013482:Superoxide Dismutase