Ginsenoside Rg5 increases cardiomyocyte resistance to ischemic injury through regulation of mitochondrial hexokinase-II and dynamin-related protein 1.
Ginsenoside Rg5 increases cardiomyocyte resistance to ischemic injury through regulation of mitochondrial hexokinase-II and dynamin-related protein 1.
复制标题
人参皂苷 Rg5 通过调节线粒体己糖激酶-II 和动力相关蛋白 1 增强心肌细胞对缺血性损伤的抵抗力
DOI：
10.1038/cddis.2017.43
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发表时间：
2017-02-23
影响因子：
9
通讯作者：
Qi LW
中科院分区：
文献类型：
--
作者：
Yang YL;Li J;Liu K;Zhang L;Liu Q;Liu B;Qi LW
己糖激酶-II(HK-II)和动力蛋白相关蛋白1(Drp1)对线粒体功能的调节是不同的。本研究旨在探讨人参皂苷Rg5(Rg5)对心肌细胞线粒体HK-II和DRp1的调节作用。饱和棕榈酸(PA)刺激通过抑制心肌细胞丙酮酸脱氢酶(PDH)活性，增加乳酸蓄积，诱导细胞酸化，导致HK-II从线粒体解离。RG5通过对抗脂肪酸氧化，提高PDH活性，防止细胞酸化，有助于保护线粒体HK-II。HK-II与线粒体的结合阻止了线粒体Drp1的募集，而Drp1的激活则降低了线粒体HK-II的含量，表明与线粒体的结合是相互控制的。Rg5促进Akt易位到线粒体，增加HK-II与线粒体的结合，同时协同抑制Drp1募集和线粒体分裂。AKT抑制剂Triciriine或用小干扰RNA敲除Akt可减弱Rg5的作用，表明Rg5通过Akt激活抑制了Drp1的激活，促进了HK-II的结合。RG5可阻止线粒体通透性转换孔的开放，增加ATP的生成，从而增强心肌细胞对缺氧/复氧损伤的抵抗能力。同时，在异丙肾上腺素诱导的小鼠缺血心脏模型中，Rg5通过增加HK-II结合和减少Drp1向线粒体的募集来防止细胞凋亡。综上所述，这些发现不仅确立了人参皂苷在心脏保护中先前未知的作用，而且还表明线粒体HK-II结合和DRp1募集可以作为治疗的靶点，以防止心脏缺血损伤。
Hexokinase-II (HK-II) and dynamin-related protein 1 (Drp1) regulate mitochondrial function differently. This study was designed to investigate the cardioprotective effect of ginsenoside Rg5 (Rg5) with emphasis on the regulation of mitochondrial HK-II and Drp1. Saturated acid palmitate (PA) stimulation increased lactate accumulation and induced cellular acidification by impairing the activity of pyruvate dehydrogenase (PDH) in cardiomyocytes, leading to HK-II dissociation from mitochondria. Rg5 improved PDH activity and prevented cellular acidification by combating fatty-acid oxidation, contributing to protecting mitochondrial HK-II. HK-II binding to mitochondria prevented mitochondrial Drp1 recruitment, whereas Drp1 activation decreased the content of mitochondrial HK-II, demonstrating the reciprocal control for binding to mitochondria. Rg5 promoted Akt translocation to mitochondria and increased HK-II binding to mitochondria while coordinately suppressing Drp1 recruitment and mitochondrial fission. Akt inhibitor triciribine or knockdown of Akt with small interfering RNA diminished the effects of Rg5, indicating that Rg5 inhibited Drp1 activation and promoted HK-II mitochondrial binding through Akt activation. Rg5 prevented the opening of mitochondrial permeability transition pore and increased ATP production, resultantly increasing cardiomyocyte resistance to hypoxia/reoxygenation injury. Meanwhile, Rg5 prevented cell apoptosis with increased HK-II binding and reduced Drp1 recruitment to mitochondria in isoproterenol-induced ischemic heart of mice. Taken together, these findings not only established a previously unrecognized role of ginsenosides in cardioprotection but also suggest that mitochondrial HK-II binding and Drp1 recruitment could be targeted therapeutically to prevent ischemic injury in the heart.