Li Chuyun, Lai Hengli, Cai Xinyong, Liu Yuanyuan, Hong Lang, Huang Xiao, Shao Liang
Department of Medical Oncology, The First People's Hospital of Fuzhou, The Fifth Affiliated Hospital of Nanchang University.
Department of Cardiology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College.
Int Heart J. 2023 Mar 31;64(1):60-70. doi: 10.1536/ihj.22-283. Epub 2023 Jan 31.
Doxorubicin (DOX) may cause multiple side effects, which include cardiotoxicity. Hence, to ascertain the impact of thioredoxin reductase 2 (TXNRD2) and cytochrome c, somatic (CYCS) on DOX-induced oxidative stress (OS) in cardiomyocytes and mouse myocardium, this study was implemented. DOX was utilized to treat cardiomyocytes and mice, and TXNRD2 and CYCS expression in cell supernatant and mouse myocardial tissues was detected. TXNRD2 and/or CYCS were overexpressed in DOX-induced cardiomyocytes and mice. In cardiomyocytes, cell viability and the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and glutathione (GSH) were measured. In mice, pathologic changes of the heart, ejection fraction (EF), fractional shortening (FS), and heart weight (HW) /tibial length (TL) ratio, and the contents of lactic dehydrogenase (LDH), creatine kinase-MB (CK-MB), and cardiac troponin I (cTnI) were analyzed. To assess the binding between TXNRD2 and CYCS, coimmunoprecipitation and glutathione S-transferase pull-down assays were performed. TXNRD2 and CYCS were downregulated in DOX-treated cardiomyocytes and mice. Mechanistically, TXNRD2 interacted with CYCS. Overexpression of TXNRD2 or CYCS augmented viability and SOD, CAT, and GSH levels but reduced ROS and MDA contents in DOX-induced cardiomyocytes, which was further facilitated by simultaneous overexpression of TXNRD2 or CYCS. Moreover, TXNRD2 or CYCS upregulation improved the pathologic changes in myocardial tissues, along with increases in EF, FS, and HW/TL ratio of the heart and SOD, CAT, and GSH levels and decreases in LDH, CK-MB, cTnI, ROS, and MDA levels. TXNRD2 coordinated with CYCS to alleviate DOX-induced OS in cardiomyocytes and mouse myocardium.
阿霉素（DOX）可能会引发多种副作用，其中包括心脏毒性。因此，为了确定硫氧还蛋白还原酶2（TXNRD2）和细胞色素c体（CYCS）对DOX诱导的心肌细胞和小鼠心肌氧化应激（OS）的影响，开展了本研究。使用DOX处理心肌细胞和小鼠，并检测细胞上清液和小鼠心肌组织中TXNRD2和CYCS的表达。在DOX诱导的心肌细胞和小鼠中过表达TXNRD2和/或CYCS。在心肌细胞中，测量细胞活力以及活性氧（ROS）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、丙二醛（MDA）和谷胱甘肽（GSH）的水平。在小鼠中，分析心脏的病理变化、射血分数（EF）、缩短分数（FS）以及心脏重量（HW）/胫骨长度（TL）比值，以及乳酸脱氢酶（LDH）、肌酸激酶同工酶MB（CK-MB）和心肌肌钙蛋白I（cTnI）的含量。为了评估TXNRD2与CYCS之间的结合，进行了免疫共沉淀和谷胱甘肽S-转移酶下拉试验。在DOX处理的心肌细胞和小鼠中，TXNRD2和CYCS表达下调。机制上，TXNRD2与CYCS相互作用。TXNRD2或CYCS的过表达增加了DOX诱导的心肌细胞的活力以及SOD、CAT和GSH水平，但降低了ROS和MDA含量，TXNRD2或CYCS的同时过表达进一步促进了这一作用。此外，TXNRD2或CYCS的上调改善了心肌组织的病理变化，同时心脏的EF、FS和HW/TL比值增加，SOD、CAT和GSH水平升高，而LDH、CK-MB、cTnI、ROS和MDA水平降低。TXNRD2与CYCS协同作用，减轻DOX诱导的心肌细胞和小鼠心肌中的氧化应激。
