通过抑制S -亚硝基谷胱甘肽还原酶改善心脏骤停与复苏的预后
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Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase
背景与目的
方 法
成年野生型(WT) C57BL/6和GSNOR缺失(GSNOR−/−) 小鼠经氯化钾诱导心脏骤停后立即复苏。恢复自主循环(ROSC) 15分钟后，WT小鼠随机给予GSNOR抑制剂、SPL-334.1或生理盐水作为安慰剂。评估死亡率、神经预后、GSNOR活性和s -亚硝基化蛋白水平。在心脏骤停后的患者、施行心脏手术前的患者和健康志愿者的血浆样本中测量血浆GSNOR活性。
结 果
GSNOR活性在小鼠血浆和多种器官中均有增强，尤其是脑组织中。CA/CPR后6小时，脑内s -亚硝基化蛋白水平下降。服用SPL-334.1后可削弱大脑、心脏、肝脏、脾脏和血浆中的GSNOR活性增强，并使大脑中s -亚硝基化蛋白水平得以恢复。抑制GSNOR可减轻CA/CPR后WT小鼠的缺血性脑损伤并提高存活率( SPL-334.1组81.8% vs. 安慰剂组36.4%,Log Rank P=0.031)。同样，GSNOR缺失可防止大脑中s -亚硝基化蛋白数量的减少，减轻脑损伤，并改善CA/CPR后的神经恢复和存活率。GSNOR抑制和缺失均减弱CA/CPR诱发的血脑屏障破坏。心脏骤停后的患者血浆GSNOR活性高于心脏手术前患者或健康志愿者（P<0.0001）。停药后患者血浆GSNOR活性与初始乳酸水平呈正相关（Spearman rs=0.48, P=0.045）。
结 论
心脏骤停和心肺复苏可激活GSNOR ，减少脑内S-亚硝化蛋白的数量。药物抑制或基因敲除GSNOR 可通过恢复CA/CPR后小鼠大脑中的S -亚硝基化蛋白水平来预防缺血性脑损伤并提高存活率。我们的研究表明，GSNOR是一种新型的脑损伤后生物标志物，同时也是改善心脏骤停预后的分子靶点。
原始文献摘要
Hayashida K, Bagchi A, Miyazaki Y, et al. Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase[J]. Circulation,2019 ,139(6):815–827.
Background: The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR).
Methods: Adult wild-type (WT) C57BL/6 and GSNOR-deleted (GSNOR−/−) mice were subjected to potassium chloride-induced cardiac arrest and subsequently resuscitated. Fifteen minutes after a return of spontaneous circulation (ROSC), WT mice were randomized to receive the GSNOR inhibitor, SPL-334.1, or normal saline as placebo. Mortality, neurological outcome, GSNOR activity, and levels of S-nitrosylated proteins were evaluated. Plasma GSNOR activity was measured in plasma samples obtained from post-cardiac arrest patients, pre-operative cardiac surgery patients, and healthy volunteers.
Results: GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in WT mice after CA/CPR (81.8% in SPL-334.1 vs. 36.4% in placebo, Log Rank P=0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-cardiac arrest patients had higher plasma GSNOR activity than did pre-operative cardiac surgery patients or healthy volunteers (P<0.0001). Plasma GSNOR activity was positively correlated with initial lactate levels in post-arrest patients (Spearman rs=0.48, P=0.045).
Conclusions: Cardiac arrest and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of post-arrest brain injury as well as a molecular target to improve outcomes after cardiac arrest.
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翻译：冯玉蓉 编辑：何幼芹 审校：王贵龙