芦丁通过调节 microRNA-125b-1-3p 介导的 JunD 信号通路来预防吡柔比星所致心脏毒性。
Rutin protects against pirarubicin-induced cardiotoxicity by adjusting microRNA-125b-1-3p-mediated JunD signaling pathway.
机构信息
Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, 1266 Fujin Road, Changchun, Jilin, 130021, China.
The Third Affiliated Hospital to The Jinzhou Medical University, No. 5-2 Heping Road, Jinzhou, Liaoning, 120001, China.
出版信息
Mol Cell Biochem. 2020 Mar;466(1-2):139-148. doi: 10.1007/s11010-020-03696-9. Epub 2020 Feb 3.
Pirarubicin (THP), an anthracycline drug, is widely used as a basic therapeutic agent for the treatment of carcinoma and lymphatic malignant tumor. However, it exerts irreversible cardiotoxicity in varying degrees. At present, dexrazoxane (DZR) is the only cardioprotective agent used to treat anthracycline drug-induced cardiotoxicity, but it may reduce the anticancer effect of anthracycline drugs, causing severe granulocytopenia and other adverse reactions. Therefore, it is necessary to discover more effective and less toxic drugs for the treatment of THP-induced cardiotoxicity. The present study aimed to investigate the effects and possible mechanisms of rutin (RUT) against THP-induced cardiomyocyte injury. An in vitro cardiomyocyte injury model of THP-treated murine immortalized cardiomyocytes (HL-1) was used in this study. The results showed that RUT markedly increased the viability of HL-1 cells through protection against THP-induced cardiomyocyte injury. Furthermore, RUT significantly inhibited myocardial oxidative insult by adjusting the levels of intracellular reactive oxygen species (ROS). Our data also indicated that RUT activated JunD signaling pathways, thereby affecting the expression levels of some apoptotic proteins by decreasing miR-125b-1-3p expression level. In addition, intracellular ROS level significantly increased in HL-1 cells treated with THP after miR-125b-1-3p mimic transfection, whereas the expression of JunD was downregulated and that of some apoptotic proteins was upregulated. However, this effect was markedly reversed by RUT. Therefore, we inferred that the protective effect of RUT on THP cardiotoxicity was achieved through regulation of the JunD gene by miR-125b-1-3p. This experiment revealed the protective effect of RUT on THP-induced cardiotoxicity at the non-coding RNA level and provided a theoretical foundation for the application of RUT as a protective agent against THP cardiotoxicity.
吡柔比星（THP）是一种蒽环类药物，广泛用作治疗癌和淋巴恶性肿瘤的基本治疗剂。然而，它在不同程度上表现出不可逆的心脏毒性。目前，右雷佐生（DZR）是唯一用于治疗蒽环类药物引起的心脏毒性的心脏保护剂，但它可能会降低蒽环类药物的抗癌作用，导致严重的粒细胞减少等不良反应。因此，有必要发现更有效和毒性更低的药物来治疗 THP 引起的心脏毒性。本研究旨在探讨芦丁（RUT）对 THP 诱导的心肌细胞损伤的作用及可能机制。本研究采用 THP 处理的鼠永生化心肌细胞（HL-1）体外心肌细胞损伤模型。结果表明，RUT 通过保护 THP 诱导的心肌细胞损伤显著提高 HL-1 细胞的活力。此外，RUT 通过调节细胞内活性氧（ROS）水平显著抑制心肌氧化损伤。我们的数据还表明，RUT 激活 JunD 信号通路，从而通过降低 miR-125b-1-3p 表达水平来影响某些凋亡蛋白的表达水平。此外，THP 处理后 HL-1 细胞中 miR-125b-1-3p 模拟转染后细胞内 ROS 水平显著升高，而 JunD 表达下调，某些凋亡蛋白表达上调。然而，RUT 明显逆转了这一效应。因此，我们推断 RUT 对 THP 心脏毒性的保护作用是通过 miR-125b-1-3p 调节 JunD 基因实现的。该实验在非编码 RNA 水平揭示了 RUT 对 THP 诱导的心脏毒性的保护作用，为 RUT 作为 THP 心脏毒性保护剂的应用提供了理论基础。
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