Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China.
Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, China.
Biomed Res Int. 2020 Oct 19;2020:5923572. doi: 10.1155/2020/5923572. eCollection 2020.
Doxorubicin (DOX) is an effective anticancer drug, but its therapeutic use is limited by its cardiotoxicity. The principal mechanisms of DOX-induced cardiotoxicity are oxidative stress and apoptosis in cardiomyocytes. Orosomucoid 1 (ORM1), an acute-phase protein, plays important roles in inflammation and ischemic stroke; however, the roles and mechanisms of ORM1 in DOX-induced cardiotoxicity remain unknown. Therefore, in the present study, we aimed to investigate the function of ORM1 in cardiomyocytes experiencing DOX-induced oxidative stress and apoptosis. A DOX-induced cardiotoxicity animal model was established in C57BL/6 mice by administering an intraperitoneal injection of DOX (20 mg/kg), and the control group was intraperitoneally injected with the same volume of sterilized saline. The effects were assessed after 7 d. Additionally, H9c2 cells were stimulated with DOX (10 M) for 24 h. The results showed decreased ORM1 and increased oxidative stress and apoptosis after DOX stimulation in vivo and in vitro. ORM1 overexpression significantly reduced DOX-induced oxidative stress and apoptosis in H9c2 cells. ORM1 significantly increased the expression of nuclear factor-like 2 (Nrf2) and its downstream protein heme oxygenase 1 (HO-1) and reduced the expression of the lipid peroxidation end product 4-hydroxynonenal (4-HNE) and the level of cleaved caspase-3. In addition, Nrf2 silencing reversed the effects of ORM1 on DOX-induced oxidative stress and apoptosis in cardiomyocytes. In conclusion, ORM1 inhibited DOX-induced oxidative stress and apoptosis in cardiomyocytes by regulating the Nrf2/HO-1 pathway, which might provide a new treatment strategy for DOX-induced cardiotoxicity.
多柔比星（DOX）是一种有效的抗癌药物，但由于其心脏毒性，其治疗用途受到限制。DOX 诱导的心脏毒性的主要机制是心肌细胞中的氧化应激和细胞凋亡。乳球蛋白 1（ORM1）是一种急性期蛋白，在炎症和缺血性中风中发挥重要作用；然而，ORM1 在 DOX 诱导的心脏毒性中的作用和机制尚不清楚。因此，在本研究中，我们旨在研究 ORM1 在经历 DOX 诱导的氧化应激和细胞凋亡的心肌细胞中的功能。通过腹腔注射 DOX（20mg/kg）建立 C57BL/6 小鼠 DOX 诱导的心脏毒性动物模型，对照组腹腔注射等体积无菌生理盐水。7d 后评估效果。此外，用 DOX（10μM）刺激 H9c2 细胞 24h。结果显示，体内和体外 DOX 刺激后 ORM1 减少，氧化应激和细胞凋亡增加。ORM1 过表达可显著减轻 H9c2 细胞中 DOX 诱导的氧化应激和细胞凋亡。ORM1 显著增加核因子样 2（Nrf2）及其下游蛋白血红素加氧酶 1（HO-1）的表达，减少脂质过氧化终产物 4-羟壬烯醛（4-HNE）的表达和裂解 caspase-3 的水平。此外，Nrf2 沉默逆转了 ORM1 对心肌细胞中 DOX 诱导的氧化应激和细胞凋亡的作用。总之，ORM1 通过调节 Nrf2/HO-1 通路抑制心肌细胞中 DOX 诱导的氧化应激和细胞凋亡，为 DOX 诱导的心脏毒性提供了一种新的治疗策略。
