The First Clinical Medical College, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
Zhejiang university, Hangzhou 310000, Zhejiang, China.
Toxicol Appl Pharmacol. 2022 Oct 1;452:116179. doi: 10.1016/j.taap.2022.116179. Epub 2022 Jul 29.
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.
多柔比星（DOX）是一种有效的蒽环类抗肿瘤药物。然而，其剂量依赖性的心脏毒性限制了其临床应用。染料木黄酮是一种天然的异黄酮糖苷，对调节凋亡相关信号通路至关重要。在这项研究中，我们评估了染料木黄酮对多柔比星诱导的心脏毒性的可能保护作用，并阐明了潜在的分子机制。分别在多柔比星处理的 H9C2 细胞和大鼠中进行了体外和体内评估。首先，通过尾静脉注射多柔比星诱导 Wistar 大鼠心肌病。然后，将 DOX+Ononin30 和 DOX+Ononin60 组大鼠在 DOX 处理前两周进行灌胃给予染料木黄酮。将 H9C2 细胞用载体或 DOX 加或不加染料木黄酮处理。接下来，使用 3-TYP 来确定内质网（ER）应激与 SIRT3 表达之间的关系。染料木黄酮处理改善了超声心动图确定的多柔比星诱导的心肌损伤。此外，染料木黄酮部分恢复了多柔比星诱导的心脏功能障碍；预先给予染料木黄酮后，左心室射血分数（LVEF）和左心室收缩分数缩短（LVFS）增加。此外，染料木黄酮抑制了大鼠心肌细胞和 H9C2 细胞中多柔比星诱导的 ER 应激和细胞凋亡。与对照组相比，DOX 处理组的 Bax/Bcl-2 比值以及 78-kD 葡萄糖调节蛋白（GRP78）和 CCAAT 增强子结合蛋白（CHOP）表达水平更高，但染料木黄酮处理改善了这些参数。这些作用与 SIRT3 活性有关。此外，3-TYP 阻断了染料木黄酮的保护作用。因此，染料木黄酮通过抑制 ER 应激和细胞凋亡对多柔比星诱导的心脏毒性产生积极影响，这可能是通过刺激 SIRT3 途径介导的。
