阿霉素心脏毒性的斑马鱼模型研究:氧化应激与Wnt信号通路的机制解析

Abstract

Adriamycin (ADR), one of the most effective broad-spectrum antitumor chemotherapeutic agents in clinical practice, is used to treat solid tumors as well as hematological malignancies in adults and children. However, long-term ADR use causes several adverse reactions, including time- and dose-dependent cardiotoxicity, which limit its clinical application. In addition, the mechanism by which ADR induces cardiotoxicity remains unclear. Therefore, we used zebrafish as animal models to evaluate ADR toxicity during embryonic heart development owing to the similarity of this process in zebrafish to that in humans. Exposure of zebrafish embryos to 1.25, 2.5, and 5 mg/L ADR induced abnormal embryonic development, with the occurrence of cardiac malformations, pericardial edema, decreased movement speed and activity, and increased distance between the venous sinus and the arterial bulb (SV-BA). ADR exposure induced dysregulated cardiogenesis during the precardiac mesoderm formation period. We also observed irregular expression of cardiac-related genes, an upregulation of apoptotic gene expression, and a dose-dependent increase in oxidative stress levels. Furthermore, oxidative stress-induced apoptosis exerted deleterious effects on cardiac development in zebrafish embryos, and treatment with astaxanthin (ATX) alleviated these heart defects. ADR- and Wnt pathway-related genes exhibited good energy and spatial matching, and ADR upregulated the Wnt signaling pathway in zebrafish. Moreover, IWR-1 effectively alleviated ADR-induced heart defects. In conclusion, we demonstrated that the toxic effects of ADR on cardiac development in zebrafish embryos could provide a theoretical basis for explaining the pathogenesis of ADR-induced cardiotoxicity, which occurs through the upregulation of oxidative stress and Wnt signaling pathway, as well as its prevention and treatment in humans. These