Li Lin, Li Jinghao, Wang Qilong, Zhao Xin, Yang Dongli, Niu Lu, Yang Yanze, Zheng Xianxian, Hu Limin, Li Yuhong
Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Front Pharmacol. 2020 Jun 5;11:815. doi: 10.3389/fphar.2020.00815. eCollection 2020.
Shenmai injection (SMI), as a patented traditional Chinese medicine, is extracted from Panax ginseng and Ophiopogon japonicus. It commonly used in the treatment of cardiovascular disease and in the control of cardiac toxicity induced by doxorubicin (DOX) treatment. However, its anti-cardiotoxicity mechanism remains unknown. The purpose of this study was to investigate the underlying mitochondrial protective mechanisms of SMI on DOX-induced myocardial injury. The cardioprotective effect of SMI against DOX-induced myocardial damage was evaluated in C57BL/6 mice and H9c2 cardiomyocytes. , myocardial injury, apoptosis and phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt)/glycogen synthase kinase 3 beta (GSK-3β) signaling pathway related proteins were measured. , apoptosis, mitochondrial superoxide, mitochondrial membrane potential, mitochondrial morphology, levels of mitochondrial fission/fusion associated proteins, mitochondrial respiratory function, and AMP-activated protein kinase (AMPK) activity were assessed. To further elucidate the regulating effects of SMI on AMPK and PI3K/Akt/GSK-3β signaling pathway, compound C and LY294002 were utilized. , SMI decreased mortality rate, levels of creatine kinase, and creatine kinase-MB. SMI significantly prevented DOX-induced cardiac dysfunction and apoptosis, decreased levels of Bax/Bcl-2 and cleaved-Caspase3, increased levels of PI3K, p-Akt, and p-GSK-3β. , SMI rescued DOX-injured H9c2 cardiomyocytes from apoptosis, excessive mitochondrial reactive oxygen species production and descending mitochondrial membrane potential, which were markedly suppressed by LY294002. SMI increased ratio of L-OPA1 to S-OPA1, levels of AMPK phosphorylation, and DRP1 phosphorylation (Ser637) in order to prevent DOX-induced excessive mitochondrial fission and insufficient mitochondrial fusion. In conclusion, SMI prevents DOX-induced cardiotoxicity, inhibits mitochondrial oxidative stress and mitochondrial fragmentation through activation of AMPK and PI3K/Akt/GSK-3β signaling pathway.
参麦注射液（SMI）是一种专利中药，由人参和麦冬提取而成。它常用于治疗心血管疾病以及控制阿霉素（DOX）治疗引起的心脏毒性。然而，其抗心脏毒性机制尚不清楚。本研究的目的是探讨参麦注射液对阿霉素诱导的心肌损伤潜在的线粒体保护机制。在C57BL/6小鼠和H9c2心肌细胞中评估了参麦注射液对阿霉素诱导的心肌损伤的心脏保护作用。检测了心肌损伤、凋亡以及与磷酸肌醇3激酶（PI3K）/蛋白激酶B（PKB/Akt）/糖原合酶激酶3β（GSK-3β）信号通路相关的蛋白。评估了凋亡、线粒体超氧化物、线粒体膜电位、线粒体形态、线粒体分裂/融合相关蛋白水平、线粒体呼吸功能以及AMP激活蛋白激酶（AMPK）活性。为了进一步阐明参麦注射液对AMPK和PI3K/Akt/GSK-3β信号通路的调节作用，使用了化合物C和LY294002。参麦注射液降低了死亡率、肌酸激酶水平以及肌酸激酶同工酶MB水平。参麦注射液显著预防了阿霉素诱导的心脏功能障碍和凋亡，降低了Bax/Bcl-2和裂解的Caspase3水平，提高了PI3K、p-Akt和p-GSK-3β水平。参麦注射液使阿霉素损伤的H9c2心肌细胞免于凋亡、过量的线粒体活性氧生成以及线粒体膜电位下降，而LY294002显著抑制了这些作用。参麦注射液提高了L-OPA1与S-OPA1的比例、AMPK磷酸化水平以及动力相关蛋白1（DRP1）磷酸化（Ser637）水平，以防止阿霉素诱导的过度线粒体分裂和线粒体融合不足。总之，参麦注射液通过激活AMPK和PI3K/Akt/GSK-3β信号通路预防阿霉素诱导的心脏毒性，抑制线粒体氧化应激和线粒体碎片化。
