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Salidroside inhibits doxorubicin-induced cardiomyopathy by modulating a ferroptosis-dependent pathway

红景天苷 药理学 阿霉素 脂质过氧化 线粒体 化学 心脏毒性 生物化学 氧化应激 体内 生物 毒性 遗传学 生物技术 有机化学 化疗
作者
Hang Chen,Ji Zhu,Yifei Le,Jieli Pan,Ying Liu,Zhijun Liu,Cui Wang,Xiaobing Dou,Dezhao Lu
出处
期刊:Phytomedicine [Elsevier]
卷期号:99: 153964-153964 被引量:74
标识
DOI:10.1016/j.phymed.2022.153964
摘要

Doxorubicin-induced cardiotoxicity (DIC) limits the clinical application of the drug in treatment of cancers and imposes a severe health burden on the patients. Therefore, there is an urgent need to develop alternative therapeutic strategies or drugs to minimize DIC. Salidroside is a phenylpropanoid glycoside extracted from Rhodiola rosea with multiple biological effects such as anti-inflammation and antioxidant properties. However, its mechanism of action in DIC is still poorly understood.The present study was aimed to investigate the role of salidroside in DIC and associated mechanism of action for the described effects.Cardiac dysfunction was induced through treatment of mice with doxorubicin in vivo and in vitro. The mechanism of action of salidroside was investigated using western blot assay, qPCR, immunofluorescence, histochemistry, echocardiography, and high-content imaging system.Results of the current study found that treatment of mice with salidroside significantly improved doxorubicin-induced cardiac dysfunction, ferroptosis-like cell damage, and fibrosis in vivo. Further, it was noted that salidroside inhibited ferroptosis in vivo and in vitro by limiting iron accumulation, restoring GPX4-dependent antioxidant capacity, and preventing lipid peroxidation at the cellular or mitochondrial levels. Mechanistically, salidroside inhibited DOX-induced mitochondrial ROS, Fe2+, and lipid peroxidation as well as restored mitochondrial membrane potential by promoting mitochondrial biogenesis, improving mitochondrial iron-sulfur clusters, and restoring mitochondrial OXPHOS complexes, thereby improving mitochondrial function. In addition, AMPK is a key protein that coordinates mitochondria, metabolism, and ferroptosis. Therefore, it was found that compound C (CC), an AMPK inhibitor, disrupted the regulation of cellular lipid metabolism and mitochondrial function of salidroside as well as led to failure of the protective effect of salidroside against ferroptotic cell death.The present study evidently demonstrated the cardioprotective effects of salidroside against doxorubicin-induced cardiomyopathy. Further, salidroside markedly down-regulated ferroptotic cell death by activating AMPK-dependent signaling pathways including regulating abnormal fatty acid metabolism and maintaining mitochondrial function. Therefore, salidroside is can be exploited to develop a novel medication for clinical DIC and salidroside may represent a novel treatment that improves recovery from DIC by targeting ferroptosis.
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