Wang Min, Wang Rui-Ying, Zhou Jia-Hui, Xie Xue-Heng, Sun Gui-Bo, Sun Xiao-Bo
Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China.
Oxid Med Cell Longev. 2020 Aug 31;2020:2415269. doi: 10.1155/2020/2415269. eCollection 2020.
Calenduloside E (CE) is a natural triterpenoid saponin isolated from (Miq.) Seem., a well-known traditional Chinese medicine. Our previous studies have shown that CE exerts cardiovascular protective effects both and . However, its role in myocardial ischemia/reperfusion injury (MIRI) and the mechanism involved are currently unknown. Mitochondrial dynamics play a key role in MIRI. This study investigated the effects of CE on mitochondrial dynamics and the signaling pathways involved in myocardial ischemia/reperfusion (MI/R). The MI/R rat model and the hypoxia/reoxygenation (H/R) cardiomyocyte model were established in this study. CE exerted significant cardioprotective effects and by improving cardiac function, decreasing myocardial infarct size, increasing cardiomyocyte viability, and inhibiting cardiomyocyte apoptosis associated with MI/R. Mechanistically, CE restored mitochondrial homeostasis against MI/R injury through improved mitochondrial ultrastructure, enhanced ATP content and mitochondrial membrane potential, and reduced mitochondrial permeability transition pore (MPTP) opening, while promoting mitochondrial fusion and preventing mitochondrial fission. However, genetic silencing of OPA1 by siRNA abolished the beneficial effects of CE on cardiomyocyte survival and mitochondrial dynamics. Moreover, we demonstrated that CE activated AMP-activated protein kinase (AMPK) and treatment with the AMPK inhibitor, compound C, abolished the protective effects of CE on OPA1 expression and mitochondrial function. Overall, this study demonstrates that CE is effective in mitigating MIRI by modulating AMPK activation-mediated OPA1-related mitochondrial fusion.
金盏花苷E（CE）是从一种著名的传统中药旋覆花（Inula japonica Thunb. (Miq.) Seem.）中分离出的一种天然三萜皂苷。我们之前的研究表明，CE在体内和体外均发挥心血管保护作用。然而，其在心肌缺血/再灌注损伤（MIRI）中的作用及相关机制目前尚不清楚。线粒体动力学在MIRI中起关键作用。本研究调查了CE对线粒体动力学以及心肌缺血/再灌注（MI/R）相关信号通路的影响。本研究建立了MI/R大鼠模型和缺氧/复氧（H/R）心肌细胞模型。CE通过改善心脏功能、减小心肌梗死面积、提高心肌细胞活力以及抑制与MI/R相关的心肌细胞凋亡，在体内和体外均发挥了显著的心脏保护作用。机制上，CE通过改善线粒体超微结构、增加ATP含量和线粒体膜电位、减少线粒体通透性转换孔（MPTP）开放，同时促进线粒体融合并防止线粒体分裂，恢复了对抗MI/R损伤的线粒体稳态。然而，通过小干扰RNA（siRNA）对OPA1进行基因沉默消除了CE对心肌细胞存活和线粒体动力学的有益作用。此外，我们证明CE激活了腺苷酸活化蛋白激酶（AMPK），用AMPK抑制剂化合物C处理消除了CE对OPA1表达和线粒体功能的保护作用。总体而言，本研究表明CE通过调节AMPK激活介导的OPA1相关线粒体融合有效减轻MIRI。
