Salvianolic Acid B Improves Postresuscitation Myocardial and Cerebral Outcomes in a Murine Model of Cardiac Arrest: Involvement of Nrf2 Signaling Pathway
Salvianolic Acid B Improves Postresuscitation Myocardial and Cerebral Outcomes in a Murine Model of Cardiac Arrest: Involvement of Nrf2 Signaling Pathway
复制标题
丹酚酸 B 改善心脏骤停小鼠模型中复苏后心肌和大脑的转归：Nrf2 信号通路的参与
DOI：
10.1155/2020/1605456
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发表时间：
2020-07-02
影响因子：
--
通讯作者：
He, Ben
中科院分区：
文献类型：
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作者：
Ji, Qing-Qi;Li, Yan-Jie;He, Ben
尽管心肺复苏（CPR）得到了改善，但心脏骤停（CA）的生存率和结局仍然令人沮丧。丹参酸B（SaliviacidB，Sal B）是从丹参中提取的一种抗心肌缺血性心脏病的有效成分。本研究的目的是了解Sal B是否改善小鼠CA/CPR后的心脏和神经系统结局。雌性C57 BL/6小鼠接受8分钟的CA，通过静脉注射氯化钾（KCl）诱导，然后进行CPR。心肺复苏30秒后，将小鼠随机盲法静脉注射Sal B（20 mg/kg）或溶媒（生理盐水）。分别于心肺复苏前及复苏后3小时内测定血流动力学参数及左心功能指标。与溶媒处理的小鼠相比，Sal B给药导致成功复苏的动物恢复自发循环（ROSC）所需的时间显著减少。心肌性能，包括心输出量和左心室收缩（dp/dtmax）和舒张（dp/dtmin）功能，明显改善三个小时内的ROSC在Sal B治疗的小鼠。此外，Sal B抑制CA/CPR诱导的心肌细胞凋亡，并保护线粒体的形态和功能。Sal B通过下调Keap 1的表达，显著促进Nrf 2核转位，导致HO-1和NQO 1等抗氧化酶的表达，从而对抗CA/CPR引起的氧化损伤。Sal B的上述抗凋亡和抗氧化作用在体外模型中用siRNA沉默Nrf 2基因的设置中受损。这些改善与更好的神经功能和复苏后72小时的生存率增加（75% vs. 40%，p < 0.05）相关。我们的研究结果表明，Sal B通过激活Nrf 2抗氧化信号通路改善了CA小鼠模型的心脏功能和神经功能结局，这可能代表了治疗CA的新治疗策略。
Survival and outcome of cardiac arrest (CA) are dismal despite improvements in cardiopulmonary resuscitation (CPR). Salvianolic acid B (Sal B), extracted from Salvia miltiorrhiza, has been investigated for its cardioprotective properties in cardiac remodeling and ischemic heart disease, but less is known about its role in CA. The aim of this study was to learn whether Sal B improves cardiac and neurologic outcomes after CA/CPR in mice. Female C57BL/6 mice were subjected to eight minutes of CA induced by an intravenous injection of potassium chloride (KCl), followed by CPR. After 30 seconds of CPR, mice were blindly randomized to receive either Sal B (20 mg/kg) or vehicle (normal saline) intravenously. Hemodynamic variables and indices of left ventricular function were determined before CA and within three hours after CPR, the early postresuscitation period. Sal B administration resulted in a remarkable decrease in the time required for the return of spontaneous circulation (ROSC) in animals that successfully resuscitated compared to the vehicle-treated mice. Myocardial performance, including cardiac output and left ventricular systolic (dp/dtmax) and diastolic (dp/dtmin) function, was clearly ameliorated within three hours of ROSC in the Sal B-treated mice. Moreover, Sal B inhibited CA/CPR-induced cardiomyocyte apoptosis and preserved mitochondrial morphology and function. Mechanistically, Sal B dramatically promoted Nrf2 nuclear translocation through the downregulation of Keap1, which resulted in the expression of antioxidant enzymes, including HO-1 and NQO1, thereby counteracted the oxidative damage in response to CA/CPR. The aforementioned antiapoptotic and antioxidant effects of Sal B were impaired in the setting of gene silencing of Nrf2 with siRNA in vitro model. These improvements were associated with better neurological function and increased survival rate (75% vs. 40%, p < 0.05) up to 72 hours postresuscitation. Our findings suggest that the administration of Sal B improved cardiac function and neurological outcomes in a murine model of CA via activating the Nrf2 antioxidant signaling pathway, which may represent a novel therapeutic strategy for the treatment of CA.