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
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nangjing, China.
Department of Biostatistics, School of Global Public Health, New York University, New York, NY, United States.
Front Pharmacol. 2022 May 5;13:879870. doi: 10.3389/fphar.2022.879870. eCollection 2022.
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 , 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 (HO)-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 HO-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.
缺血心肌中产生的活性氧（ROS）可诱导心肌细胞损伤和死亡，导致心脏重塑。铁死亡是一种由铁依赖性氧化应激引起的新型细胞死亡，是心肌细胞中的一种重要死亡机制。然而，尚不清楚氧化应激产物是否会进一步诱导铁死亡并加重心肌细胞损伤。栀子苷（GEN）是[具体植物名称]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，我们评估了铁死亡在心肌氧化损伤中的作用以及GEN对心肌铁死亡的保护作用。我们首先在柠檬酸铁铵（FAC）处理的心肌细胞中检测到铁过载、大量ROS和脂质过氧化，这些都是铁死亡的典型特征。铁过载诱导的氧化应激和铁死亡加重了心肌细胞损伤，而GEN处理可显著减轻这种损伤。在过氧化氢（HO）诱导的细胞中也一致发现了类似的铁死亡表型变化，GEN处理同样可使其逆转。有趣的是，RNA结合蛋白Grsf1在翻译水平直接上调Gpx4，在心肌氧化损伤后被GEN激活。特异性敲低Grsf1增加了它们对铁死亡的敏感性，并削弱了GEN在HO处理的心肌细胞中的心脏保护作用。此外，GEN处理降低了心肌梗死（MI）大鼠的铁过载和脂质过氧化，从而对抗心脏缺血损伤。总体而言，我们的研究揭示了与心肌缺血相关的氧化应激和铁死亡的发病机制，并表明GEN通过激活Grsf1/GPx4轴对预防心肌损伤具有抗氧化和抗铁死亡作用，可作为潜在的治疗靶点。
