Geniposide Possesses the Protective Effect on Myocardial Injury by Inhibiting Oxidative Stress and Ferroptosis via Activation of the Grsf1/GPx4 Axis.
Geniposide Possesses the Protective Effect on Myocardial Injury by Inhibiting Oxidative Stress and Ferroptosis via Activation of the Grsf1/GPx4 Axis.
复制标题
京尼平苷通过激活 Grsf1/GPx4 轴抑制氧化应激和铁死亡，对心肌损伤具有保护作用
DOI：
10.3389/fphar.2022.879870
复制
发表时间：
2022
影响因子：
5.6
通讯作者：
Shen, Jianping
中科院分区：
文献类型：
--
作者：
Shen, Yuehong;Wang, Xindong;Shen, Xinyu;Wang, Yue;Wang, Shulin;Zhang, Yunyun;Yao, Xiaoming;Xu, Yijiao;Sang, Ming;Pan, Jiamin;Qin, Yu;Zhou, Qian;Shen, Jianping
关键词：
缺血心肌中产生的活性氧（ROS）可诱导心肌细胞损伤和死亡，导致心脏重构。铁凋亡是由铁依赖性氧化应激引起的一种新型细胞死亡，是心肌细胞的一种重要死亡机制。然而，目前尚不清楚氧化应激产物是否会进一步诱导铁凋亡，加重心肌细胞损伤。京尼平苷（GEN）是栀子（Gardenia jasminoides J. Ellis）的主要活性成分，具有天然抗氧化活性和心脏保护作用。在此，我们评价了铁凋亡在心肌氧化损伤中的作用以及GEN对心肌铁凋亡的保护作用。我们首先检测到柠檬酸铁铵（FAC）处理的心肌细胞中的铁过载，大量的ROS和脂质过氧化，这是铁凋亡的典型特征。铁超载引起的氧化应激和铁凋亡加重心肌细胞损伤，GEN治疗可显著减轻心肌细胞损伤。在过氧化氢（H2 O2）诱导的细胞中发现了类似的铁凋亡表型变化，GEN处理也能逆转这种变化。有趣的是，RNA结合蛋白Grsf 1，直接上调Gpx 4在翻译水平，被激活GEN心肌氧化损伤后。在H2 O2处理的心肌细胞中，Grsf 1的特异性敲低增加了它们对铁凋亡的敏感性，并减弱了GEN的心脏保护作用。此外，GEN治疗减少了心肌梗死（MI）大鼠的铁超载和脂质过氧化反应，从而对抗心脏缺血性损伤。总之，本研究揭示了心肌缺血相关的氧化应激和铁凋亡的发病机制，提示GEN通过激活Grsf 1/GPx 4轴发挥抗氧化和抗铁凋亡作用，预防心肌损伤，是潜在的治疗靶点。
Reactive oxygen species (ROS) produced in the ischemic myocardium can induce cardiomyocyte injury and death, resulting in cardiac remodeling. Ferroptosis, known as a newly type of cell death caused by iron-dependent oxidative stress, which is an essential death mechanism in cardiomyocytes. However, it is unclear whether oxidative stress products can further induce ferroptosis and aggravate cardiomyocyte injury. Geniposide (GEN), a major active component of Gardenia jasminoides J. Ellis, possesses the natural antioxidant activity and cardioprotective effect. Herein, we evaluated the role of ferroptosis in myocardial oxidative injury and the protective effect of GEN on myocardial ferroptosis. We first detected iron overload, massive ROS, and lipid peroxidation in ferric ammonium citrate (FAC)-treated cardiomyocytes, which were typical characteristics of ferroptosis. The iron overload-induced oxidative stress and ferroptosis aggravated cardiomyocyte injury, which were significantly alleviated by GEN treatment. Similar phenotypic changes of ferroptosis were consistently discovered in hydrogen peroxide (H2O2)-induced cells, which were reversed by GEN treatment as well. Interestingly, the RNA-binding protein Grsf1, which directly upregulated Gpx4 at the translational level, was activated by GEN following myocardial oxidative injury. The specific knockdown of Grsf1 increased their sensitivity to ferroptosis and weakened the cardioprotective effect of GEN in H2O2-treated cardiomyocytes. Moreover, GEN treatment reduced iron overload and lipid peroxidation in myocardial infarction (MI) rats, thereby fighting against the cardiac ischemic injury. Collectively, our study revealed the pathogenesis of oxidative stress and ferroptosis associated with myocardial ischemia, and indicated the antioxidant and anti-ferroptosis effects of GEN on preventing myocardial injury by activating the Grsf1/GPx4 axis, serving as a potential therapeutic target.
登录
查看更多内容
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
9
作者：
Park, Tae-Jun;Park, Jei Hyoung;Lee, Sang Chul
通讯作者：
Lee, Sang Chul
影响因子：
4.1
作者：
Lu, W.;Zhao, Y.;Wang, K.
通讯作者：
Wang, K.
影响因子：
3.2
作者：
Jiang, Ting;Cheng, Hui;Li, Qinglin
通讯作者：
Li, Qinglin
心肌铁蛋白 H 缺失通过 Slc7a11 介导的铁死亡促进心肌病
影响因子：
20.1
作者：
Fang, Xuexian;Cai, Zhaoxian;Wang, Fudi
通讯作者：
Wang, Fudi