Liu Xiaoman, Li Danlei, Pi Wenhu, Wang Bin, Xu Shasha, Yu Lei, Yao Lei, Sun Zhenzhu, Jiang Jianjun, Mi Yafei
Department of Cardiology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China; Laboratory of Cardiovascular Disease, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China.
Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Department of Radiation Oncology, Affiliated Taizhou hospital of Wenzhou Medical University, Linhai 317000, Zhejiang Province, China.
Int Immunopharmacol. 2022 Dec;113(Pt A):109379. doi: 10.1016/j.intimp.2022.109379. Epub 2022 Oct 29.
Doxorubicin (DOX) is an effective and widely used anticancer drug but has limited clinical applicability because of its cardiotoxicity. Ferroptosis plays a key role in DOX-induced cardiac damage and cardiomyocyte cell death. The inhibition of ferroptosis reverses DOX-induced cardiotoxicity (DIC). LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, protects against DIC. However, the mechanism of action of LCZ696, especially its effect on ferroptosis, is incompletely understood. This study investigates the cardioprotective effects of LCZ696 on DIC in vivo and in vitro.Cardiotoxicity was induced in Wistar rats by tail intravenous injection of 2.5 mg/kg DOX once a week for six weeks. Rats and H9c2 cells were treated with or without LCZ696 to determine the cardioprotective role and underlying mechanisms of LCZ696 against DIC. To assess the role of SIRT3 and correlated pathways in ferroptosis, SIRT3 knockout was performed using lentiviral vectors, and AKT was inhibited with LY294002. LCZ696 significantly attenuated DIC by decreasing the concentrations of lipid reactive oxygen species and malondialdehyde and increasing the levels of glutathione peroxidase-4 and reduced glutathione in cells and heart tissues. Moreover, LCZ696 remodeled myocardial structures and improved heart ventricular function in DOX-treated rats. LCZ696 treatment increased SIRT3 expression and deacetylated its target gene SOD2, and these changes were mediated by AKT activation. SIRT3 knockdown and AKT inhibition induced lipid peroxidation and reduced the protective effect of LCZ696 in H9c2 cells. Collectively,LCZ696 prevents DIC by inhibiting ferroptosis via AKT/SIRT3/SOD2 signaling pathway activation. Thus, LZC696 is a potential therapeutic strategy for DIC.
阿霉素（DOX）是一种有效且广泛使用的抗癌药物，但由于其心脏毒性，临床适用性有限。铁死亡在DOX诱导的心脏损伤和心肌细胞死亡中起关键作用。抑制铁死亡可逆转DOX诱导的心脏毒性（DIC）。LCZ696是一种一流的血管紧张素受体脑啡肽酶抑制剂，可预防DIC。然而，LCZ696的作用机制，尤其是其对铁死亡的影响，尚未完全明确。本研究调查了LCZ696在体内和体外对DIC的心脏保护作用。通过每周一次尾静脉注射2.5mg/kg DOX，持续六周，诱导Wistar大鼠发生心脏毒性。对大鼠和H9c2细胞进行LCZ696处理或不处理，以确定LCZ696对DIC的心脏保护作用及其潜在机制。为了评估SIRT3及相关信号通路在铁死亡中的作用，使用慢病毒载体进行SIRT3基因敲除，并用LY294002抑制AKT。LCZ696通过降低细胞和心脏组织中脂质活性氧和丙二醛的浓度，并提高谷胱甘肽过氧化物酶-4和还原型谷胱甘肽的水平，显著减轻了DIC。此外，LCZ696重塑了心肌结构，并改善了DOX处理大鼠的心室功能。LCZ696处理增加了SIRT3的表达，并使其靶基因SOD2去乙酰化，这些变化是由AKT激活介导的。SIRT3基因敲低和AKT抑制诱导脂质过氧化，并降低了LCZ696对H9c2细胞的保护作用。总体而言，LCZ696通过激活AKT/SIRT3/SOD2信号通路抑制铁死亡，从而预防DIC。因此，LCZ696是一种治疗DIC的潜在策略。
