Orosomucoid 1 Attenuates Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes via Nrf2 Signaling.
Orosomucoid 1 Attenuates Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes via Nrf2 Signaling.
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Orosumucoid 1 通过 Nrf2 信号传导减弱多柔比星诱导的心肌细胞氧化应激和细胞凋亡
DOI：
10.1155/2020/5923572
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发表时间：
2020
影响因子：
--
通讯作者：
Han Y
中科院分区：
文献类型：
--
作者：
Cheng X;Liu D;Xing R;Song H;Tian X;Yan C;Han Y
阿霉素（DOX）是一种有效的抗癌药物，但其治疗用途因其心脏毒性而受到限制。 DOX 诱导的心脏毒性的主要机制是心肌细胞的氧化应激和凋亡。 Orosumucoid 1 (ORM1) 是一种急性时相蛋白，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仍不清楚。因此，在本研究中，我们旨在研究 ORM1 在经历 DOX 诱导的氧化应激和凋亡的心肌细胞中的功能。 C57BL/6小鼠腹腔注射DOX（20mg/kg）建立DOX心脏毒性动物模型，对照组腹腔注射等体积无菌生理盐水。 7天后评估效果。此外，用 DOX (10μM) 刺激 H9c2 细胞 24 小时。结果显示，体内和体外 DOX 刺激后，ORM1 降低，氧化应激和细胞凋亡增加。 ORM1 过表达显着降低了 H9c2 细胞中 DOX 诱导的氧化应激和细胞凋亡。 ORM1显着增加核因子样2（Nrf2）及其下游蛋白血红素加氧酶1（HO-1）的表达，并降低脂质过氧化终产物4-羟基壬烯醛（4-HNE）的表达和裂解的caspase-3的水平。此外，Nrf2沉默逆转了ORM1对DOX诱导的心肌细胞氧化应激和细胞凋亡的影响。总之，ORM1通过调节Nrf2/HO-1通路抑制DOX诱导的心肌细胞氧化应激和凋亡，这可能为DOX诱导的心脏毒性提供新的治疗策略。
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 μM) 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.
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