Lin Zhi-Hui, Xiang Hua-Qiang, Yu Yong-Wei, Xue Yang-Jing, Wu Chang, Lin Cong, Ji Kang-Ting
Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.
Intensive Care Unit, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
FASEB J. 2024 May 31;38(10):e23677. doi: 10.1096/fj.202400222RR.
Although the use of Doxorubicin (Dox) is extensive in the treatment of malignant tumor, the toxic effects of Dox on the heart can cause myocardial injury. Therefore, it is necessary to find an alternative drug to alleviate the Dox-induced cardiotoxicity. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin, which is an active ingredient of Artemisia annua. The study investigates the effects of DHA on doxorubicin-induced cardiotoxicity and ferroptosis, which are related to the activation of Nrf2 and the regulation of autophagy. Different concentrations of DHA were administered by gavage for 4 weeks in mice. H9c2 cells were pretreated with different concentrations of DHA for 24 h in vitro. The mechanism of DHA treatment was explored through echocardiography, biochemical analysis, real-time quantitative PCR, western blotting analysis, ROS/DHE staining, immunohistochemistry, and immunofluorescence. In vivo, DHA markedly relieved Dox-induced cardiac dysfunction, attenuated oxidative stress, alleviated cardiomyocyte ferroptosis, activated Nrf2, promoted autophagy, and improved the function of lysosomes. In vitro, DHA attenuated oxidative stress and cardiomyocyte ferroptosis, activated Nrf2, promoted clearance of autophagosomes, and reduced lysosomal destruction. The changes of ferroptosis and Nrf2 depend on selective degradation of keap1 and recovery of lysosome. We found for the first time that DHA could protect the heart from the toxic effects of Dox-induced cardiotoxicity. In addition, DHA significantly alleviates Dox-induced ferroptosis through the clearance of autophagosomes, including the selective degradation of keap1 and the recovery of lysosomes.
尽管阿霉素（Dox）在恶性肿瘤治疗中应用广泛，但其对心脏的毒性作用可导致心肌损伤。因此，有必要寻找一种替代药物来减轻阿霉素诱导的心脏毒性。双氢青蒿素（DHA）是青蒿素的半合成衍生物，青蒿素是青蒿的活性成分。本研究调查了DHA对阿霉素诱导的心脏毒性和铁死亡的影响，这与Nrf2的激活和自噬的调节有关。不同浓度的DHA通过灌胃给予小鼠4周。H9c2细胞在体外用不同浓度的DHA预处理24小时。通过超声心动图、生化分析、实时定量PCR、蛋白质免疫印迹分析、ROS/DHE染色、免疫组织化学和免疫荧光来探索DHA的治疗机制。在体内，DHA显著减轻了阿霉素诱导的心脏功能障碍，减轻了氧化应激，缓解了心肌细胞铁死亡，激活了Nrf2，促进了自噬，并改善了溶酶体功能。在体外，DHA减轻了氧化应激和心肌细胞铁死亡，激活了Nrf2，促进了自噬体的清除，并减少了溶酶体破坏。铁死亡和Nrf2的变化取决于keap1的选择性降解和溶酶体的恢复。我们首次发现DHA可以保护心脏免受阿霉素诱导的心脏毒性作用。此外，DHA通过清除自噬体，包括keap1的选择性降解和溶酶体的恢复，显著减轻了阿霉素诱导的铁死亡。
