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

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

  • Toxicol Appl Pharmacol. 2022 Oct 1;452:116179. doi: 10.1016/j.taap.2022.116179.
Hanlin Zhang 1 Jingfan Weng 2 Shimin Sun 1 Jiedong Zhou 3 Qi Yang 4 Xingxiao Huang 2 Jing Sun 1 Miaohong Pan 3 Jufang Chi 5 Hangyuan Guo 6
Affiliations

Affiliations

  • 1 The First Clinical Medical College, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
  • 2 Zhejiang university, Hangzhou 310000, Zhejiang, China.
  • 3 Medical college of Shaoxing University, Shaoxing 312000, Zhejiang, China.
  • 4 Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang, China.
  • 5 Department of Cardiology, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing 312000, Zhejiang, China.
  • 6 The First Clinical Medical College, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; Medical college of Shaoxing University, Shaoxing 312000, Zhejiang, China. Electronic address: guohangyuan@zju.edu.cn.
Abstract

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.

Keywords

Cardiotoxicity; Doxorubicin; ER stress; Ononin; SIRT3.

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