Jie Song, Wenying Guo, Lebo Sun
Department of Cardiothoracic Surgery, Ningbo Medical Center Lihuili Hospital of Ningbo University, No. 57, Xingning Rd, Ningbo City 315041, Zhejiang Province, China.
Department of Digestive, Ningbo Medical Center Lihuili Hospital of Ningbo University, No. 57, Xingning Rd, Ningbo City 315041, Zhejiang Province, China.
Cardiovasc Ther. 2024 Dec 7;2024:5538740. doi: 10.1155/cdr/5538740. eCollection 2024.
Doxorubicin (DOX) is a widely used antitumor drug; however, its use is limited by the risk of serious cardiotoxicity. Dehydroevodiamine (DHE) is a quinazoline alkaloid which has antiarrhythmic effects. The aim of this study was to investigate the protective effect of DHE on doxorubicin-induced cardiotoxicity (DIC) and its potential mechanism. Rat H9c2 cardiomyocytes were exposed to DOX for 24 h to establish a DOX-induced cardiomyocyte injury model. DHE and ErbB inhibitor AG1478 were used to treat H9c2 cells to investigate their effects. Cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays were used to evaluate cell viability. Flow cytometry and caspase-3 activity assay were used to detect apoptosis. Western blot was used to detect the expression levels of apoptosis-related proteins and neuregulin-1 (NRG1)/ErbB pathway-related proteins. The levels of proinflammatory cytokines and markers of oxidative stress were also detected, respectively. Quantitative polymerase chain reaction (qPCR) was used to detect mRNA expression levels of hub genes. DHE enhanced cardiomyocyte viability and decreased LDH release in a concentration- and time-dependent manner. DHE also significantly inhibited DOX-induced cardiomyocyte apoptosis, inflammation, and oxidative stress. Bioinformatics analysis showed that the protective mechanism of DHE against DIC was related to ErbB signaling pathway. DOX treatment significantly reduced NRG1, p-ErbB2, and p-ErbB4 protein expression levels in cardiomyocytes, while DHE pretreatment reversed this effect. ErbB inhibitor AG1478 reversed the protective effect of DHE on cardiomyocytes. DHE protects cardiomyocytes against DOX by regulating NRG1/ErbB pathway. DHE may be a potential agent for the prevention and treatment of DIC.
阿霉素（DOX）是一种广泛使用的抗肿瘤药物；然而，其使用受到严重心脏毒性风险的限制。去氢吴茱萸碱（DHE）是一种具有抗心律失常作用的喹唑啉生物碱。本研究的目的是探讨DHE对阿霉素诱导的心脏毒性（DIC）的保护作用及其潜在机制。将大鼠H9c2心肌细胞暴露于DOX 24小时以建立阿霉素诱导的心肌细胞损伤模型。使用DHE和表皮生长因子受体（ErbB）抑制剂AG1478处理H9c2细胞以研究它们的作用。使用细胞计数试剂盒-8（CCK-8）和乳酸脱氢酶（LDH）释放试验评估细胞活力。使用流式细胞术和半胱天冬酶-3活性测定法检测细胞凋亡。蛋白质免疫印迹法用于检测凋亡相关蛋白和神经调节蛋白-1（NRG1）/ErbB信号通路相关蛋白的表达水平。还分别检测了促炎细胞因子水平和氧化应激标志物。定量聚合酶链反应（qPCR）用于检测核心基因的mRNA表达水平。DHE以浓度和时间依赖性方式增强心肌细胞活力并降低LDH释放。DHE还显著抑制DOX诱导的心肌细胞凋亡炎症和氧化应激。生物信息学分析表明，DHE对DIC的保护机制与ErbB信号通路有关。DOX处理显著降低心肌细胞中NRG1、磷酸化表皮生长因子受体2（p-ErbB2）和磷酸化表皮生长因子受体4（p-ErbB4）蛋白表达水平，而DHE预处理可逆转这种作用。ErbB抑制剂AG1478可逆转DHE对心肌细胞的保护作用。DHE通过调节NRG1/ErbB信号通路保护心肌细胞免受DOX损伤。DHE可能是预防和治疗DIC的潜在药物。
