Increased PINK1/Parkin-mediated mitophagy explains the improved brain protective effects of slow rewarming following hypothermia after cardiac arrest in rats
Increased PINK1/Parkin-mediated mitophagy explains the improved brain protective effects of slow rewarming following hypothermia after cardiac arrest in rats
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PINK1/Parkin 介导的线粒体自噬增加解释了大鼠心脏骤停后体温过低后缓慢复温对大脑保护作用的改善
DOI：
10.1016/j.expneurol.2020.113326
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发表时间：
2020-08-01
影响因子：
5.3
通讯作者：
Cui, Derong
中科院分区：
文献类型：
--
作者：
Hu, Yue;Sun, Dawei;Cui, Derong
心脏骤停（CA）后脑缺血再灌注（I/R）可诱导线粒体功能障碍，线粒体自噬及时清除受损线粒体可预防脑I/R损伤。治疗性低温（TH）已成为CA后恢复自然循环患者复苏后护理的重要组成部分。既往研究表明，TH可激活线粒体自噬并发挥保护作用；然而，最佳复温速率和TH后复温的潜在机制在很大程度上仍未得到解释。在这里，我们研究了不同复温速率的影响，以及有丝分裂是否参与了复温。冷却4 h，窒息CA 5 min后，将Sprague-Dawley大鼠随机分为常温、低温、慢复温（0.5℃/h）和快复温（4℃/h）组。低温组保持低温至组织收获，慢速复温组和快速复温组复温时间分别为6 h和45 min。我们发现，慢速复温大鼠的72 h存活率高于常温大鼠和快速复温大鼠（分别为70%、25.71%和50%），且神经功能缺损评分（nds）更高，中位数分别为57.33、26和28.83。此外，我们探索了这一过程的潜在机制，发现在缓慢复温组中，PINK1/ parkinson介导的线粒体自噬在低温过程中被激活，而在快速复温组中被抑制。缓慢复温大鼠进一步抑制线粒体自噬导致细胞严重凋亡，平均NDS从58.39降低到33.11，表明线粒体自噬具有保护作用。此外，快速复温组表现出PINK1表达和线粒体自噬活性不足，活性氧（ROS）积累明显。总的来说，我们的研究结果强调了在低温后缓慢复温过程中PINK1/帕金森介导的有丝分裂的神经保护作用。
Cerebral ischemia-reperfusion (I/R) after cardiac arrest (CA) induces mitochondrial dysfunction, and the timely removal of damaged mitochondria by mitophagy is reported to protect against cerebral I/R injury. Therapeutic hypothermia (TH) has become an important component of postresuscitation care for patients who return to spontaneous circulation after CA. Previous studies have shown that TH can activate mitophagy and can contribute a protective effect; however, the optimal rewarming rate and underlying mechanism of rewarming following TH remain largely unexplained. Here, we investigated the effects of different rewarming rates and whether mitophagy is involved in rewarming. After 5 min of asphyxial CA following 4 h of cooling, Sprague-Dawley rats were randomized into the normothermia, hypothermia, slow rewarming (0.5 degrees C/h) and fast rewarming (4 degrees C/h) groups. The hypothermia group was kept cool until tissue harvest, the rewarming duration for the slow rewarming group and fast rewarming group was 6 h and 45 min, respectively. We found that slowly rewarmed rats had better survival at 72 h than normothermic rats and fast-rewarmed rats (70%, 25.71%, and 50%, respectively) and higher neurological deficit scores (NDSs), in which the medians were 57.33, 26, and 28.83, respectively. In addition, we explored the underlying mechanism during this process and found that PINK1/Parkin-mediated mitophagy was activated during hypothermia in the slow rewarming group but was inhibited in the fast rewarming group. Further inhibition of mitophagy in the slowly rewarmed rats resulted in severe apoptosis and decreased the mean NDS from 58.39 to 33.11, indicating the protective role of mitophagy. Moreover, the fast rewarming group exhibited deficiencies in PINK1 expression and mitophagy activity and marked accumulation of reactive oxygen species (ROS). Overall, our results highlighted a neuroprotective role of PINK1/Parkin-mediated mitophagy during slow rewarming after hypothermia.