Higenamine Attenuates Doxorubicin-Induced Cardiac Remodeling and Myocyte Apoptosis by Suppressing AMPK Activation.
Higenamine Attenuates Doxorubicin-Induced Cardiac Remodeling and Myocyte Apoptosis by Suppressing AMPK Activation.
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DOI：
10.3389/fcell.2022.809996
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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背景：多柔比星（DOX）作为一种有效的抗肿瘤药物，主要用于治疗实体瘤和血液系统恶性肿瘤。然而，越来越多的证据表明其心脏毒性，并且很少有解决方案被提出来对抗这种副作用。去甲乌药碱（HG）是一种天然化合物，广泛存在于许多中草药中，也是许多保健产品的成分。一些研究已经证明了其在不同模型中的心脏保护作用，但很少有人知道HG对DOX诱导的慢性心脏毒性引起的心肌损伤的潜在影响。 方法和结果：采用C57 BL/6小鼠和新生大鼠心室肌细胞（NRVMs）观察HG对DOX诱导的心肌损伤的保护作用。在小鼠中，DOX（每3天腹腔注射5 mg/kg，持续4周）显著增加心肌细胞凋亡、心脏萎缩和心功能不全，HG（每天灌胃10 mg/kg，持续4周）显著减弱。在NRVM中，DOX（3 μM，24 h）显著增加细胞凋亡和活性氧水平，同时降低超氧化物歧化酶水平和线粒体膜电位。值得注意的是，HG可以逆转DOX引起的这些病理变化。有趣的是，HG对DOX诱导的心脏毒性的保护作用不依赖于β 2肾上腺素能受体（β2-AR）的激活，β 2肾上腺素能受体（β2-AR）已知介导HG对抗缺血/再灌注诱导的心脏凋亡的作用。此外，HG减弱了磷酸化腺苷激活蛋白激酶（AMPK）的异常激活。AMPK激动剂（AICAR）可消除HG的上述药理作用。 结论：总之，我们的结果表明，HG减轻DOX诱导的慢性心肌损伤通过抑制AMPK激活和ROS的产生。
Background: As an effective antitumor drug, doxorubicin (DOX) is primarily used to treat solid tumors and hematologic malignancies. However, increasing evidence has emerged indicating its cardiotoxicity, and few solutions have been proposed to counter this side effect. Higenamine (HG) is a natural compound widely found in many Chinese herbs and also serves as a component in many healthcare products. Several studies have demonstrated its cardioprotective effect in different models, but little is known about the underlying influences of HG against myocardial damage from DOX-induced chronic cardiotoxicity. Methods and Results: C57BL/6 mice and neonatal rat ventricular cardiomyocytes (NRVMs) were used to evaluate the cardioprotective effect of HG against DOX-induced myocardial damage. In mice, DOX (intraperitoneally injected 5 mg/kg every 3 days for 4 weeks) significantly increased cardiomyocyte apoptosis, cardiac atrophy, and cardiac dysfunction, which were significantly attenuated by HG (intragastrically administered with 10 mg/kg every day for 4 weeks). In NRVMs, DOX (3 μM for 24 h) significantly increased cell apoptosis and the level of reactive oxygen species while reducing the level of superoxide dismutase and mitochondrial membrane potential. Remarkably, HG can reverse these pathological changes caused by DOX. Interestingly, the protective effect of HG on DOX-induced cardiotoxicity was independent of the activation of the beta-2 adrenergic receptor (β2-AR), known for mediating the effect of HG on antagonizing ischemia/reperfusion-induced cardiac apoptosis. Furthermore, HG attenuated the abnormal activation of phosphorylated adenosine-activated protein kinase (AMPK). Consistently, AMPK agonists (AICAR) can eliminate these pharmacological actions of HG. Conclusion: Collectively, our results suggested that HG alleviated DOX-induced chronic myocardial injury by suppressing AMPK activation and ROS production.