Role of Nrf2-Gpx4 signaling pathway in Shenmai injection-induced reduction of myocardial ischemia-reperfusion injury: relationship with ferroptosis in rats

Mei Shenglan; Xia Zhongyuan; Wu Xiaojing; Lei Shaoqing; Meng Qingtao; Qiu Zhen; Zhou Bin; Ming Hao; Zhou Jinjian

doi:10.3760/cma.j.issn.0254-1416.2019.11.031

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• 重症医学 •

Nrf2-Gpx4信号通路在参麦注射液减轻大鼠心肌缺血再灌注损伤中的作用：与铁死亡的关系

中华麻醉学杂志, 2019,39(11) : 1395-1398. DOI: 10.3760/cma.j.issn.0254-1416.2019.11.031

摘要

目的

评价核因子E2相关因子2(Nrf2)-谷胱甘肽过氧化物酶4(GPX4)信号通路在参麦注射液减轻大鼠心肌缺血再灌注损伤中的作用及其与铁死亡的关系。

方法

SPF级健康成年雄性SD大鼠48只，体重220～250 g，采用随机数字表法分为4组(n＝12)：假手术组(S组)、心肌缺血再灌注组(IR组)、参麦注射液组(SM组)和参麦注射液＋Nrf2抑制剂组(SMM组)采用结扎冠状动脉左前降支30 min，再灌注120 min的方法制备大鼠心肌缺血再灌注损伤模型。S组只穿线不结扎；SM组再灌注前即刻静脉注射参麦注射液9 ml/kg；SMM组缺血30 min前腹腔注射Nrf2抑制剂ML385 30 mg/kg，再灌注前即刻静脉注射参麦注射液9 ml/kg。于再灌注120 min时每组随机取6只大鼠，左心室取血后处死，取心尖组织在透射电镜下观察超微结构，采用ELISA法测定血清cTnI浓度，比色法测定心肌组织Fe^2＋、MDA含量和SOD活性，Western blot法检测Nrf2、GPX4和长链脂酰辅酶A合成酶4(ACSL4)的表达，另每组取6只大鼠，测定心肌梗死面积。

结果

与S组比较，IR组、SM组和SMM组心肌梗死面积、血清cTnI浓度、心肌Fe^2＋和MDA含量升高，SOD活性降低，心肌Nrf2和GPX4表达下调，ACSL4表达上调(P<0.05) ；与IR组比较，SM组心肌梗死面积、血清cTnI浓度、心肌Fe^2＋和MDA含量降低，SOD活性升高，Nrf2和GPX4表达上调，ACSL4表达下调(P<0.05)，SMM组上述指标差异无统计学意义(P>0.05)；与SM组比较，SMM组心肌梗死面积、血清cTnI浓度、心肌Fe^2＋含量升高，SOD活性降低，Nrf2和GPX4表达下调，ACSL4表达上调(P<0.05)。

结论

Nrf2-Gpx4信号通路激活参与了参麦注射液减轻大鼠心肌缺血再灌注损伤的过程，与抑制铁死亡有关。

引用本文: 梅胜兰, 夏中元, 吴晓静, 等. Nrf2-Gpx4信号通路在参麦注射液减轻大鼠心肌缺血再灌注损伤中的作用：与铁死亡的关系 [J] . 中华麻醉学杂志,2019,39 (11): 1395-1398. DOI: 10.3760/cma.j.issn.0254-1416.2019.11.031

参考文献导出: Endnote NoteExpress RefWorks NoteFirst 医学文献王

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急性心肌梗死患者恢复血流后，心肌细胞结构、功能等损伤反而加重，称为心肌缺血再灌注损伤，阻止和减少心肌细胞死亡是改善和恢复心脏功能的关键。参麦主要化学成分是人参皂苷和麦冬皂苷等，具有清除氧自由基、抑制脂质过氧化反应等作用。研究表明，参麦注射液可减轻心肌缺血再灌注损伤，有必要明确其机制。铁死亡是一种与坏死、凋亡、自噬、焦亡等不同的全新细胞死亡方式^[1]，是铁离子依赖的脂质过氧化物超量蓄积引起的以线粒体改变为主的死亡方式。心肌缺血再灌注后，铁稳态调节通路被激活，铁离子堆积，活性氧生成增加，最终导致铁离子依赖的氧化损伤即铁死亡^[2]。核因子E2相关因子2(Nrf2)-谷胱甘肽过氧化物酶4(GPX4)信号通路参与了大鼠心肌缺血再灌注损伤的过程^[3,4]。本研究拟评价Nrf2-GPX4信号通路在参麦注射液减轻大鼠心肌缺血再灌注损伤中的作用及其与铁死亡的关系，为进一步明确其机制提供参考。

贡献者信息

梅胜兰

武汉大学人民医院麻醉科　430060

夏中元

武汉大学人民医院麻醉科　430060

吴晓静

武汉大学人民医院麻醉科　430060

雷少青

武汉大学人民医院麻醉科　430060

孟庆涛

武汉大学人民医院麻醉科　430060

邱珍

武汉大学人民医院麻醉科　430060

周斌

武汉大学人民医院麻醉科　430060

明浩

武汉大学人民医院麻醉科　430060

周金剑

武汉大学人民医院麻醉科　430060

通信作者

夏中元

武汉大学人民医院麻醉科　430060

Email：xiazhongyuan2005@aliyun.com

关键词

NF-E2相关因子2; 谷胱甘肽过氧化酶; 皂苷类; 心肌再灌注损伤; 细胞死亡;

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历史

出版日期：2019-11-20

收稿日期：2019-03-11

本文编辑

葛胜辉

Critical Care Medicine

Role of Nrf2-Gpx4 signaling pathway in Shenmai injection-induced reduction of myocardial ischemia-reperfusion injury: relationship with ferroptosis in rats

Mei Shenglan, Xia Zhongyuan, Wu Xiaojing, Lei Shaoqing, Meng Qingtao, Qiu Zhen, Zhou Bin, Ming Hao, Zhou Jinjian

Published 2019-11-20

Cite as Chin J Anesthesiol, 2019,39(11): 1395-1398. DOI: 10.3760/cma.j.issn.0254-1416.2019.11.031

Abstract

Objective

To evaluate the role of nuclear factor erythroid 2-related factor 2 (Nrf2)-glutathione peroxidase 4 (GPX4) signaling pathway in Shenmai injection-induced reduction of myocardial ischemia-reperfusion (I/R) injury and the relationship with ferroptosis in rats.

Methods

Forty-eight SPF healthy adult male Sprague-Dawley rats, weighing 220-250 g, were divided into 4 groups (n=12 each) by a random number table method: sham operation group (S group), myocardial I/R group (IR group), Shenmai injection group (SM group), and Shenmai injection plus Nrf2 inhibitor group (SMM group). Acute myocardial I/R injury was induced by ligating the anterior descending brach of the left coronary artery for 30 min followed by 120-min reperfusion in anesthetized rats.In SM group, Shenmai injection 9 ml/kg was intravenously injected immediately before reperfusion.In group SMM, Nrf2 inhibitor ML385 30 mg/kg was intraperitoneally injected at 30 min before ischemia, and Shenmai injection 9 ml/kg was intravenously injected immediately before reperfusion.Six rats in each group were selected at 120 min of reperfusion, blood samples were collected from the left ventricle, the rats were then sacrificed, specimens were obtained from cardiac apex for examination of the ultrastructure and for determination of serum cardiac tropomin I( cTnI) level (by enzyme-linked immunosorbent assay), contents of Fe²⁺ and malondialdehyde (MDA) and superoxide dismutase (SOD) activity (by colometry), and expression of Nrf2, GPX4 and AcylCoA synthetase longchain family member 4 (ACSL4) (by Western blot). Another 6 rats in each group were selected to measure the myocardial infarct size.

Results

Compared with group S, the myocardial infarct size, serum cTnI concentrations, and myocardial Fe²⁺ and MDA contents were significantly increased, the activity of SOD was decreased, the expression of Nrf2 and GPX4 was down-regulated, and the expression of ACSL4 was up-regulated in IR, SM and SMM groups (P<0.05). Compared with group IR, the myocardial infarct size, serum cTnI concentrations, and myocardial Fe²⁺ and MDA contents were significantly decreased, the activity of SOD was increased, the expression of Nrf2 and GPX4 was up-regulated, and the expression of ACSL4 was down-regulated in group SM (P<0.05), and no significant change was found in the parameters mentioned above in group SMM (P>0.05). Compared with group SM, the myocardial infarct size, serum cTnI concentrations, and myocardial Fe²⁺ contents were significantly increased, the activity of SOD was decreased, the expression of Nrf2 and GPX4 was down-regulated, and the expression of ACSL4 was up-regulated in group SMM (P<0.05).

Conclusion

Activation of Nrf2-Gpx4 signaling pathway is involved in Shenmai injection-induced reduction of myocardial I/R injury and is related to inhibiting ferroptosis in rats.

Key words:

NF-E2-related factor 2; Glutathione peroxidase; SAPONINS; Myocardial reperfusion injury; Cell death

Contributor Information

Mei Shenglan