背景:阿霉素(DOX)诱导的心脏毒性(DIC)是其临床应用的主要障碍。探索减轻DIC的替代治疗分子或药物是必不可少的。WGX50,一种来自花椒的有机提取物,具有抗炎和抗氧化的生物活性,然而,其在DIC中的作用和机制尚不清楚。
方法:我们在体外和体内建立了DOX诱导的心脏毒性模型。超声心动图和组织学分析用于确定小鼠心脏损伤的严重程度。心肌损伤标志物cTnT,CK-MB,ANP,BNP,和铁凋亡相关指标Fe2+,MDA,和GPX4使用ELISA测量,RT-qPCR,和蛋白质印迹分析。用透射电镜观察线粒体的形态。线粒体膜电位的水平,线粒体ROS,使用JC-1、MitoSOX™检测脂质ROS,和C11-BODIPY581/591探头。
结果:我们的发现表明WGX50通过抑制线粒体ROS和铁凋亡来保护DOX诱导的心脏毒性。在体内,WGX50可有效缓解阿霉素引起的心功能不全,心脏损伤,纤维化,线粒体损伤,和氧化还原失衡。体外,WGX50通过降低线粒体膜电位水平和增加线粒体ATP产生来保持线粒体功能。此外,WGX50减少铁积累和线粒体ROS,增加GPX4表达,并调节脂质代谢以抑制DOX诱导的铁凋亡。
结论:综合来看,WGX50通过线粒体ROS和铁凋亡途径保护DOX诱导的心脏毒性,这为WGX50作为心脏保护的有希望的候选药物提供了新的见解。
Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear.
We established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes.
Our findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced ferroptosis.
Taken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection.