Hu Xiaoliang, Li Cheng, Wang Qian, Wei Zhixing, Chen Taizhong, Wang Yuepeng, Li Yigang
Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Pharmacol. 2022 Apr 26;13:872057. doi: 10.3389/fphar.2022.872057. eCollection 2022.
Doxorubicin (DOX) is limited in clinical application because of its cardiotoxicity. Oxidative stress and apoptosis are crucial in DOX-induced cardiac injury. Dimethyl fumarate (DMF) is an FDA-approved oral drug with powerful effects to reduce oxidative stress and apoptosis through the Nrf2 pathway. This study was aimed to determine whether DMF can protect against DOX-induced cardiac injury. We used both neonatal rat cardiomyocytes (NRCMs) and DOX-induced cardiac toxicity to explore the effects of DMF. The results showed that DMF significantly improved cell viability and morphology in NRCMs. In addition, DMF alleviated DOX-induced cardiac injury in rats, as evidenced by decreased CK-MB, LDH levels, improved survival rates, cardiac function, and pathological changes. Moreover, DMF significantly inhibited cardiac oxidative stress by reducing MDA levels and increasing GSH, SOD, and GSH-px levels. And DMF also inhibited DOX-induced cardiac apoptosis by modulating Bax, Bcl-2 and cleaved caspase-3 expression. Moreover, DMF exerted its protective effects against DOX by promoting Nrf2 nuclear translocation, which activated its downstream antioxidant gene Hmox1. Silencing of Nrf2 attenuated the protective effects of DMF in NRCMs as manifested by increased intracellular oxidative stress, elevated apoptosis levels, and decreased cell viability. In addition, DMF showed no protective effects on the viability of DOX-treated tumor cells, which suggested that DMF does not interfere with the antitumor effect of DOX . In conclusion, our data confirmed that DMF alleviated DOX-induced cardiotoxicity by regulating oxidative stress and apoptosis through the Nrf2 pathway. DMF may serve as a new candidate to alleviate DOX-related cardiotoxicity in the future.
阿霉素（DOX）因其心脏毒性在临床应用中受到限制。氧化应激和细胞凋亡在DOX诱导的心脏损伤中起关键作用。富马酸二甲酯（DMF）是一种经美国食品药品监督管理局（FDA）批准的口服药物，具有通过Nrf2途径减轻氧化应激和细胞凋亡的强大作用。本研究旨在确定DMF是否能预防DOX诱导的心脏损伤。我们使用新生大鼠心肌细胞（NRCMs）和DOX诱导的心脏毒性来探究DMF的作用。结果表明，DMF显著改善了NRCMs的细胞活力和形态。此外，DMF减轻了大鼠DOX诱导的心脏损伤，表现为肌酸激酶同工酶（CK-MB）、乳酸脱氢酶（LDH）水平降低，存活率、心脏功能改善以及病理变化减轻。此外，DMF通过降低丙二醛（MDA）水平并增加谷胱甘肽（GSH）、超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-px）水平，显著抑制心脏氧化应激。并且DMF还通过调节Bax、Bcl-2和裂解的半胱天冬酶-3的表达来抑制DOX诱导的心脏细胞凋亡。此外，DMF通过促进Nrf2核转位发挥其对DOX的保护作用，从而激活其下游抗氧化基因血红素加氧酶-1（Hmox1）。Nrf2沉默减弱了DMF在NRCMs中的保护作用，表现为细胞内氧化应激增加、凋亡水平升高和细胞活力降低。此外，DMF对DOX处理的肿瘤细胞活力没有保护作用，这表明DMF不干扰DOX的抗肿瘤作用。总之，我们的数据证实，DMF通过Nrf2途径调节氧化应激和细胞凋亡，减轻了DOX诱导的心脏毒性。未来，DMF可能成为减轻DOX相关心脏毒性的新候选药物。
