山西医科大学学报2025，Vol.56Issue(5)：534-543,10.DOI:10.13753/j.issn.1007-6611.2025.05.010
GDF11对多柔比星心脏毒性的保护作用及机制
Protective effect and mechanism of GDF11 against Doxorubicin-induced cardiotoxicity
摘要
Abstract
Objective To investigate the protective effects and mechanism of growth differentiation factor 11(GDF11)against Doxoru-bicin(DOX)-induced cardiotoxicity.Methods Eighty male C57BL/6 mice were randomly divided into four groups:Con+AAV9-null group,Con+AAV9-GDF11 group,DOX+AAV9-null group and DOX+AAV9-GDF11 group,with 20 mice in each group.Mice in Con+AAV9-GDF11 group and DOX+AAV9-GDF11 group were injected with 100 μL of AAV9-GDF11 virus via the tail vein two weeks be-fore modeling.The cardiotoxicity model was established by intraperitoneal injection of Doxorubicin.Cardiac function was assessed by echocardiography.Serum levels of creatine kinase-MB(CK-MB)and cardiac troponin Ⅰ(cTnⅠ)were measured using ELISA kits.Mean cross-sectional area of cardiomyocytes was observed by wheat germ agglutinin(WGA)staining.Myocardial fibrosis was evaluated using Masson staining.Mitochondrial morphology was observed using transmission electron microscope.ROS production was detected using DHE staining.qRT-PCR was used to detect the mRNA expressions of GDF11,Collagen1a1,Collagen3a1,and mtDNA copy number.Western blotting was used to detect the protein expressions of GDF11,glutathione peroxidase 4(GPX4),recombinant solute carrier family 7,member 11(SLC7A11),cyclooxygenase-2(COX2),nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase 1(HO-1),and NAD(P)H oxidoreductase 1(NQO-1).Results Compared with Con+AAV9-null group,GDF11 expression was de-creased(P＜0.01),cardiac systolic function was reduced(P＜0.01),serum levels of CK-MB and cTnⅠ were increased(P＜0.01),myo-cardial atrophy and fibrosis were exacerbated(P＜0.01),cardiomyocyte ferroptosis was increased(P＜0.01),myocardial lipid peroxida-tion was enhanced(P＜0.01),mitochondrial function was decreased and ROS production was increased(P＜0.01),and the expressions of Nrf2,HO-1 and NQO-1 were downregulated in DOX+AAV9-null group(P＜0.01).Compared with DOX+AAV9-null group,GDF11 expression was increased(P＜0.01),cardiac systolic function was increased(P＜0.01),serum levels of CK-MB and cTnⅠ were de-creased(P＜0.01),myocardial atrophy and fibrosis were alleviated(P＜0.01),cardiomyocyte ferroptosis was decreased(P＜0.01),myo-cardial lipid peroxidation was weakened(P＜0.01),mitochondrial function was enhanced and ROS production was decreased(P＜0.01),and the expressions of Nrf2,HO-1 and NQO-1 were upregulated DOX+AAV9-GDF11 group(P＜0.01).Conclusion GDF11 can inhibit cardiomyocyte ferroptosis and mitochondrial injury by regulating the Nrf2 signaling pathway,thereby exerting a protective effect against Doxorubicin-induced cardiotoxicity.关键词
生长分化因子11/多柔比星/心脏毒性/铁死亡/线粒体/Nrf2信号通路Key words
GDF11/Doxorubicin/cardiotoxicity/ferroptosis/mitochondria/Nrf2 signaling pathway分类
医药卫生引用本文复制引用
张玲娟,胡培静,杜占奎,徐臣年,屈欣怡..GDF11对多柔比星心脏毒性的保护作用及机制[J].山西医科大学学报,2025,56(5):534-543,10.基金项目
陕西省自然科学基础研究计划项目(2024JC-YBQN-0793) （2024JC-YBQN-0793）
