Ononin alleviates endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity by activating SIRT3

• Published in: Toxicology and applied pharmacology 2022-10, Vol.452, p.116179-116179, Article 116179
• Main Authors: Zhang, Hanlin, Weng, Jingfan, Sun, Shimin, Zhou, Jiedong, Yang, Qi, Huang, Xingxiao, Sun, Jing, Pan, Miaohong, Chi, Jufang, Guo, Hangyuan
• Format: Article
• Language: English
• Subjects: Cardiotoxicity; Doxorubicin; ER stress; Ononin; SIRT3
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2022.116179

Doxorubicin (DOX) is a potent anthracycline antineoplastic drug. However, its dose-dependent cardiotoxicity limits its clinical application. Ononin is a natural isoflavone glycoside that is crucial in modulating apoptosis-related signaling pathways. In this study, we assessed the possible cardioprotective effects of ononin in DOX-induced cardiotoxicity and elucidated the underlying molecular mechanisms. In vitro and in vivo assessments were performed using DOX-treated H9C2 cells and rats, respectively. First, DOX was injected into the tail veins of Wistar rats to induce cardiomyopathy. Next, rats in the DOX + Ononin30 and DOX + Ononin60 groups were intragastrically administered ononin two weeks before DOX treatment. H9C2 cells were treated with vehicle or DOX with or without ononin. Next, 3-TYP was used to determine the relationship between endoplasmic reticulum (ER) stress and sirtuin 3 (SIRT3) expression. Ononin treatment ameliorated DOX-induced myocardial injury as determined by echocardiography. Furthermore, ononin partially restored DOX-induced cardiac dysfunction; the left ventricular ejection fraction (LVEF) and left ventricular systolic fractional shortening (LVFS) increased after pre-treatment with ononin. Further, ononin suppressed DOX-induced ER stress and apoptosis in rat cardiomyocytes and H9C2 cells. The Bax/Bcl-2 ratio and 78-kD glucose-regulated protein (GRP78) and CCAAT enhancer-binding protein (CHOP) expression levels were higher in the DOX-treated group than in the control group but ononin treatment improved these parameters. These effects are associated with SIRT3 activity. Moreover, 3-TYP blocked the ononin-mediated protective effects. Hence, ononin positively affected DOX-induced cardiotoxicity by inhibiting ER stress and apoptosis, possibly mediated by stimulation of the SIRT3 pathway. [Display omitted] •Ononin prevented DOX-induced cardiac tissue damage in vivo.•Ononin inhibited DOX-induced apoptosis in vivo and in vitro.•Ononin inhibited DOX-induced ER stress in vivo and in vitro.•Ononin adjusted SIRT3 level in vivo and in vitro.•3-TYP(a selective SIRT3 inhibitor) reversed the effect of Ononin in vivo and in vitro.