U955, IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d'Alfort, Créteil, France.
Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK.
Basic Res Cardiol. 2019 Mar 15;114(3):18. doi: 10.1007/s00395-019-0727-0.
Hypothermia induced at the onset of ischemia is a potent experimental cardioprotective strategy for myocardial infarction. The aim of our study was to determine whether the beneficial effects of hypothermia may be due to decreasing mitochondria-mediated mechanisms of damage that contribute to the pathophysiology of ischemia/reperfusion injury. New Zealand male rabbits were submitted to 30 min of myocardial ischemia with hypothermia (32 °C) induced by total liquid ventilation (TLV). Hypothermia was applied during ischemia alone (TLV group), during ischemia and reperfusion (TLV-IR group) and normothermia (Control group). In all the cases, ischemia was performed by surgical ligation of the left anterior descending coronary artery and was followed by 3 h of reperfusion before assessment of infarct size. In a parallel study, male C57BL6/J mice underwent 30 min myocardial ischemia followed by reperfusion under either normothermia (37 °C) or conventionally induced hypothermia (32 °C). In both the models, the levels of the citric acid cycle intermediate succinate, mitochondrial complex I activity were assessed at various times. The benefit of hypothermia during ischemia on infarct size was compared to inhibition of succinate accumulation and oxidation by the complex II inhibitor malonate, applied as the pro-drug dimethyl malonate under either normothermic or hypothermic conditions. Hypothermia during ischemia was cardioprotective, even when followed by normothermic reperfusion. Hypothermia during ischemia only, or during both, ischemia and reperfusion, significantly reduced infarct size (2.8 ± 0.6%, 24.2 ± 3.0% and 49.6 ± 2.6% of the area at risk, for TLV-IR, TLV and Control groups, respectively). The significant reduction of infarct size by hypothermia was neither associated with a decrease in ischemic myocardial succinate accumulation, nor with a change in its rate of oxidation at reperfusion. Similarly, dimethyl malonate infusion and hypothermia during ischemia additively reduced infarct size (4.8 ± 2.2% of risk zone) as compared to either strategy alone. Hypothermic cardioprotection is neither dependent on the inhibition of succinate accumulation during ischemia, nor of its rapid oxidation at reperfusion. The additive effect of hypothermia and dimethyl malonate on infarct size shows that they are protective by distinct mechanisms and also suggests that combining these different therapeutic approaches could further protect against ischemia/reperfusion injury during acute myocardial infarction.
在缺血发作时诱导的低温是心肌梗死的一种有效的实验性心脏保护策略。我们的研究目的是确定低温的有益效果是否可能是由于降低了导致缺血/再灌注损伤病理生理学的线粒体介导的损伤机制。新西兰雄性兔接受 30 分钟的心肌缺血，同时通过全液体通气（TLV）诱导低温（32°C）。低温仅在缺血期间（TLV 组）、缺血和再灌注期间（TLV-IR 组）以及正常体温下（对照组）应用。在所有情况下，通过手术结扎左前降支冠状动脉进行缺血，并在评估梗塞面积之前进行 3 小时的再灌注。在一项平行研究中，雄性 C57BL6/J 小鼠在正常体温（37°C）或常规诱导的低温（32°C）下接受 30 分钟的心肌缺血和再灌注。在这两种模型中，均在不同时间评估柠檬酸循环中间产物琥珀酸和线粒体复合物 I 活性的水平。与在正常体温或低温下应用琥珀酸积累抑制剂马来酸二甲酯作为前药二甲基马来酸抑制琥珀酸积累和氧化相比，缺血期间低温的益处比较了梗塞面积。缺血期间的低温是心脏保护的，即使随后进行正常体温的再灌注也是如此。缺血期间仅低温、或缺血和再灌注期间均低温显著减小梗塞面积（TLV-IR、TLV 和对照组的危险区域分别为 2.8±0.6%、24.2±3.0%和 49.6±2.6%）。低温显著减小梗塞面积既不与缺血性心肌琥珀酸积累减少相关，也不与再灌注时其氧化速率变化相关。同样，与单独使用任何一种策略相比，缺血期间二甲基马来酸输注和低温均可额外减少梗塞面积（危险区域的 4.8±2.2%）。低温心脏保护既不依赖于缺血期间琥珀酸的积累抑制，也不依赖于再灌注时的快速氧化。低温和二甲基马来酸对梗塞面积的相加作用表明，它们通过不同的机制起保护作用，并且还表明，将这些不同的治疗方法结合起来可能会进一步防止急性心肌梗死后的缺血/再灌注损伤。
