Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Hubei Key Laboratory of Metabolic and chronic diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China.
Cell Biol Toxicol. 2022 Jun;38(3):451-467. doi: 10.1007/s10565-021-09619-8. Epub 2021 Jul 22.
Despite effective anticancer effects, the use of doxorubicin (Dox) is limited due to its side effects as cardiotoxicity. Corosolic acid (CRA) is a pentacyclic triterpene acid isolated from Lagerstroemia speciosa L. (Banaba) leaves, and it has also been shown to improve myocardial hypertrophy and myocardial infarction which expected to be used in clinical pharmaceuticals. The purpose of this study was to explore whether CRA can improve myocardial injury caused by Dox and to clarify potential mechanisms. C57 BL/6J mice and AMPKα2 knockout mice were given a single intraperitoneal (i.p.) injection of Dox (5 mg/kg) every week for 4 weeks, while normal saline (NS) was used as control. Mice were given CRA (10 mg/kg or 20 mg/kg) or equal volumes of normal saline daily after the first time i.p. injection of Dox. After 4 weeks, echocardiography, gravimetric, hemodynamic, histological, and biochemical analyses were conducted. After Dox injury, compared with the control group, CRA increased the survival rate of mice, improved the cardiac function, decreased the oxidative stress, and reduced the apoptosis. CRA may function by promoting transcription factor EB (TFEB) nuclear translocation and thus restoring autophagic flux. We also observed that CRA protected mitochondrial structure and function, which may benefit from oxidative stress reduction or TFEB activation. In vitro, the protective effect of CRA is reversed by TFEB deletion. Then, we evaluated the expression of AMPKα2/mTOR C1 signaling pathway, the main pathway of TFEB activation. In vivo and in vitro, CRA promoted TFEB nuclear translocation by activating AMPKα2/mTOR C1 signaling, while ablating AMPKα2 reversed these results and accompanied with a decrease in the ability of CRA to resist Dox-induced cardiotoxicity. Thus, we suggested that CRA activated TFEB in an AMPKα2-dependent manner to protect against Dox cardiotoxicity. This study confirms the role and mechanism of CRA in the treatment of Dox-induced cardiac injury. Dox-induced damage to autophagy includes autophagosomes maturation disorders and autophagolysosomes acidification defects, CRA restored autophagic flux, and promoted lysosomal degradation by activating TFEB in an AMPKα2-depended manner, stabilized mitochondrial function, ultimately protected against Dox-induced cardiotoxicity.
尽管阿霉素（Dox）具有有效的抗癌作用，但由于其心脏毒性等副作用，其应用受到限制。CRA 是从桃金娘科植物罗望子（Banaba）叶中分离得到的五环三萜酸，已被证明可改善心肌肥大和心肌梗死，有望用于临床药物。本研究旨在探讨 CRA 是否能改善 Dox 引起的心肌损伤，并阐明潜在的机制。C57BL/6J 小鼠和 AMPKα2 敲除小鼠每周腹腔（i.p.）注射 Dox（5mg/kg）一次，共 4 周，同时用生理盐水（NS）作为对照。第一次 i.p.注射 Dox 后，小鼠每日给予 CRA（10mg/kg 或 20mg/kg）或等量生理盐水。4 周后，进行超声心动图、称重、血流动力学、组织学和生化分析。在 Dox 损伤后，与对照组相比，CRA 提高了小鼠的存活率，改善了心脏功能，降低了氧化应激，减少了细胞凋亡。CRA 可能通过促进转录因子 EB（TFEB）核易位来发挥作用，从而恢复自噬流。我们还观察到，CRA 保护线粒体结构和功能，这可能受益于氧化应激的减少或 TFEB 的激活。体外，CRA 的保护作用可被 TFEB 缺失所逆转。然后，我们评估了 AMPKα2/mTOR C1 信号通路的表达，这是 TFEB 激活的主要途径。在体内和体外，CRA 通过激活 AMPKα2/mTOR C1 信号促进 TFEB 核易位，而 AMPKα2 的缺失则逆转了这些结果，并伴随着 CRA 抵抗 Dox 诱导的心脏毒性的能力下降。因此，我们认为 CRA 通过 AMPKα2 依赖性方式激活 TFEB 来抵抗 Dox 引起的心脏毒性。本研究证实了 CRA 在治疗 Dox 诱导的心脏损伤中的作用和机制。Dox 诱导的自噬损伤包括自噬体成熟障碍和自噬溶酶体酸化缺陷，CRA 通过激活 TFEB 在 AMPKα2 依赖性方式恢复自噬流，并促进溶酶体降解，稳定线粒体功能，最终抵抗 Dox 诱导的心脏毒性。
