Ferroptosis Is Involved in Diabetes Myocardial Ischemia/Reperfusion Injury Through Endoplasmic Reticulum Stress
Ferroptosis Is Involved in Diabetes Myocardial Ischemia/Reperfusion Injury Through Endoplasmic Reticulum Stress
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铁死亡与内质网应激引起的糖尿病心肌缺血/再灌注损伤有关
DOI：
10.1089/dna.2019.5097
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发表时间：
2019-12-06
影响因子：
3.1
通讯作者：
Xia, Zhongyuan
中科院分区：
文献类型：
--
作者：
Li, Wenyuan;Li, Wei;Xia, Zhongyuan
心肌缺血性疾病影响围手术期患者的预后。糖尿病可加重心肌损伤。本研究旨在探讨铁凋亡在糖尿病心肌缺血/再灌注损伤中的作用。内质网应激（Endoplasmic reticulum stress，ERS）是研究内质网应激是否加重心肌细胞损伤的一种重要机制。建立大鼠DM+I/R（DM + I/R）、细胞高糖（HG）、缺氧/复氧（H/R）和高糖H/R（HH/R）模型。给予铁凋亡抑制剂Ferrostatin-1、铁凋亡激动剂Erastin、ERS抑制剂Salubrinal和ERS激动剂衣霉素。检测血清肌酸激酶MB（CK-MB）、细胞活力、乳酸脱氢酶（LDH）、丙二醛（MDA）、超氧化物歧化酶（SOD）、活性氧（ROS）和细胞亚铁离子浓度。检测ACSL 4、GPX 4、ATF 4、CHOP、BCL-2、BAX水平。苏木精-伊红染色检测心肌组织病理改变。通过有创血流动力学测量监测心脏功能。采用伊文斯蓝-氯化三苯四氮唑双重染色检测心肌梗死面积。在DM+sham（DS）（或HG）和I/R（或H/R）模型中，心肌细胞损伤伴随着铁凋亡和ERS水平的增加。此外，细胞损伤更严重的大鼠海马或细胞HH/R模型。抑制心肌缺血模型中的铁凋亡可减轻ERS和心肌损伤。抑制HG、H/R和HH/R模型中H9 c2细胞的铁凋亡可减轻细胞损伤。在HH/R细胞模型中，Erastin可通过刺激铁凋亡而加重ERS和细胞损伤。同时，抑制ERS可减轻铁凋亡和细胞损伤。铁凋亡与ERS相关的神经损伤有关。抑制铁凋亡可减轻心肌损伤，为心肌缺血性疾病的治疗提供了一种新的药物。
Myocardial ischemic disease affects the prognosis in perioperative patients. Diabetes can aggravate myocardial injury. The purpose of this research is to investigate the effect of ferroptosis in the process of diabetes mellitus (DM) myocardial ischemia/reperfusion (I/R) injury (IRI). Endoplasmic reticulum stress (ERS) is investigated whether aggravates cardiomyocytes injury. Rat DM+I/R (DIR), cell high glucose (HG), hypoxia reoxygenation (H/R), and high-glucose H/R (HH/R) models were established. Ferroptosis inhibitor Ferrostatin-1, ferroptosis agonist Erastin, ERS inhibitor Salubrinal, and ERS agonist Tunicamycin were administered. Serum creatine kinase-MB (CK-MB), cell viability, lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), and cellular ferrous ion concentration were examined. The level of ACSL4, GPX4, ATF4, CHOP, BCL-2, and BAX was detected. Myocardial tissue pathological change was detected by hematoxylin-eosin staining. Cardiac function was monitored by invasive hemodynamic measurements. Evans Blue-triphenyltetrazolium chloride double staining was used to detect the myocardial infarct size. In DM+sham (DS) (or HG) and I/R (or H/R) models, cardiomyocytes were injured accompanied by increased level of ferroptosis and ERS. Moreover, the cell injury was more serious in rat DIR or cell HH/R models. Inhibition of ferroptosis in DIR model could reduce ERS and myocardial injury. Inhibition of ferroptosis in H9c2 cells HG, H/R, and HH/R models could reduce cell injury. Erastin could aggravate ERS and cell injury by stimulating ferroptosis in HH/R cell model. Meanwhile, inhibition of ERS could alleviate ferroptosis and cell injury. Ferroptosis is involved in DIR injury that is related to ERS. Moreover, inhibition of ferroptosis can alleviate DIR injury, which may provide a therapeutic regent for myocardial ischemic disease.