Sunitinib induces cardiotoxicity through modulating oxidative stress and Nrf2-dependent ferroptosis<i> in</i><i> vitro</i> and<i> in</i><i> vivo</i>

作者全名："Li, Dongjie; Song, Chengzhu; Song, Chunpu; Tian, Xinrui; Zhang, Huaibo; Zhang, Jie; Zhao, Xiaoyan"

作者地址："[Li, Dongjie; Song, Chengzhu; Song, Chunpu; Tian, Xinrui; Zhang, Huaibo; Zhao, Xiaoyan] Southwest Univ, Inst Pharmaceut Sci, Chongqing 400716, Peoples R China; [Zhang, Jie] Chongqing Med Univ, Dept Cardiol, Affiliated Hosp 2, Chongqing 400000, Peoples R China; [Zhao, Xiaoyan] Minist Educ, Engn Res Ctr Coptis Dev & Utilizat, Chongqing, Peoples R China; [Zhao, Xiaoyan] Southwest Univ, Coll Pharmaceut Sci, Chongqing 400716, Peoples R China"

通信作者："Zhang, J (通讯作者)，Chongqing Med Univ, Dept Cardiol, Affiliated Hosp 2, Chongqing 400000, Peoples R China.; Zhao, XY (通讯作者)，Southwest Univ, Coll Pharmaceut Sci, Chongqing 400716, Peoples R China."

来源：CHEMICO-BIOLOGICAL INTERACTIONS

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001136799500001

JCR分区：Q1

影响因子：5.1

年份：2024

卷号：388

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Sunitinib; Cardiotoxicity; Ferroptosis; Oxidative stress; Nrf2

摘要："SUN, a multi-targeted tyrosine kinase inhibitor, exerts cardiotoxicity which hinders its clinical use. It is necessary to elucidate molecular mechanism of SUN-induced cardiotoxicity. To elucidate molecular mechanism of SUN-induced cardiotoxicity and whether it is related to Nrf2-dependent ferroptosis, in vitro model with H9c2 cells derived from rat heart tissue and in vivo model (C57BL/6J male mouse) were used in the present study. In vivo model was established by oral treatment of SUN at dose of 10, 20, 40 mg/kg for 14 days. Body weight, ECG, plasma enzyme activities, histology staining were performed to evaluate heart function. Western-blot was per-formed to analyze the level of ferroptosis-related proteins. In vitro results indicated that SUN markedly induced ferroptosis embodied as collapsed MMP, accumulated iron and elevated ROS. In vivo results showed that SUN significantly impaired cardiac function. Abnormal electrocardiogram, increased serum CK and lactate LDH levels were significantly observed in SUN groups. Histology staining showed that SUN caused structural injuries and fibrosis deposition. Moreover, SUN increased the level of MDA and Fe2+ content, decreased the level of GSH. Both in vitro and in vivo experiments indicated that SUN reduced the expression of Nrf2, HO-1, NQO1, GPX4 and FTH1, enhanced the TfR expression. This study suggested that oxidative stress and Nrf2-dependent ferroptosis played a vital role in SUN-induced cardiotoxicity."

基金机构："Chongqing Research Program of Basic Research and Frontier Technology, China [cstc2021jcyj-msxmX0106]; Chinese Medicine Rehabilitation - the Key Discipline Constructed by Chongqing Health Bureau [2021-4322190044]"

基金资助正文："The present study was supported by the Chongqing Research Program of Basic Research and Frontier Technology, China (Grant No. cstc2021jcyj-msxmX0106) and Chinese Medicine Rehabilitation - the Key Discipline Constructed by Chongqing Health Bureau (Grant No. 2021-4322190044)."