红景天通过Nrf2/IRF1/GPX4途径抑制心肌细胞铁突变,从而改善复苏后心肌功能障碍。

Zhongjun Zheng, Jiefeng Xu, Yi Mao, Zhihan Mei, Jinjiang Zhu, Pin Lan, Xianlong Wu, Shanxiang Xu, Mao Zhang
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引用次数: 0

摘要

背景:心脏骤停(CA)和复苏后全身缺血再灌注导致心肌功能障碍,而铁蛋白沉积是导致心肌功能障碍的一种重要细胞死亡类型。被称为核因子 E2 相关因子 2(Nrf2)激活剂的茜草素(SFN)已被证实能有效缓解区域性心肌缺血再灌注损伤。本研究旨在探讨 SFN 是否能通过抑制心肌细胞铁突变及其潜在调控机制来改善复苏后心肌功能障碍:方法和结果:建立了CA和复苏猪体内模型。低氧/复氧(H/R)刺激的 AC16 心肌细胞作为体外模型模拟 CA 和复苏过程。在体外实验中,SFN降低了AC16心肌细胞H/R刺激后与铁变态反应相关的亚铁、脂质活性氧和丙二醛,增加了谷胱甘肽,进一步促进了细胞存活。从机理上讲,SFN激活Nrf2可降低干扰素调节因子1(IRF1)的表达,进而减少其与谷胱甘肽过氧化物酶4(GPX4)启动子的结合,最终恢复后者在AC16心肌细胞受到H/R刺激后的转录。在体内实验中,SFN逆转了IRF1和GPX4的异常表达,抑制了心脏铁变态反应,改善了猪CA和复苏后的心肌功能障碍:结论:SFN能有效改善CA和复苏后的心肌功能障碍,其机制可能与通过调节Nrf2/IRF1/GPX4通路抑制心肌细胞嗜铁有关。
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Sulforaphane improves post-resuscitation myocardial dysfunction by inhibiting cardiomyocytes ferroptosis via the Nrf2/IRF1/GPX4 pathway.

Background: Ferroptosis is an important type of cell death contributing to myocardial dysfunction induced by whole body ischemia reperfusion following cardiac arrest (CA) and resuscitation. Sulforaphane (SFN), known as the activator of the nuclear factor E2-related factor 2 (Nrf2), has been proven to effectively alleviate regional myocardial ischemia reperfusion injury. The present study was designed to investigate whether SFN could improve post-resuscitation myocardial dysfunction by inhibiting cardiomyocytes ferroptosis and its potential regulatory mechanism.

Methods and results: An in vivo pig model of CA and resuscitation was established. Hypoxia/reoxygenation (H/R)-stimulated AC16 cardiomyocytes was constructed as an in vitro model to simulate the process of CA and resuscitation. In vitro experiment, SFN reduced ferroptosis-related ferrous iron, lipid reactive oxygen species, and malondialdehyde, increased glutathione, and further promoted cell survival after H/R stimulation in AC16 cardiomyocytes. Mechanistically, the activation of Nrf2 with the SFN decreased interferon regulatory factor 1 (IRF1) expression, then reduced its binding to the promoter of glutathione peroxidase 4 (GPX4), and finally recovered the latter's transcription after H/R stimulation in AC16 cardiomyocytes. In vivo experiment, SFN reversed abnormal expression of IRF1 and GPX4, inhibited cardiac ferroptosis, and improved myocardial dysfunction after CA and resuscitation in pigs.

Conclusions: SFN could effectively improve myocardial dysfunction after CA and resuscitation, in which the mechanism was potentially related to the inhibition of cardiomyocytes ferroptosis through the regulation of Nrf2/IRF1/GPX4 pathway.

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