GPX4
环氧合酶
化学
支持细胞
脂质过氧化
活力测定
细胞生物学
未折叠蛋白反应
活性氧
细胞色素P450
氧化应激
生物化学
生物
谷胱甘肽过氧化物酶
超氧化物歧化酶
内分泌学
细胞
细胞凋亡
新陈代谢
酶
精子发生
作者
Huan Yang,Xuan Cai,Mengtong Qiu,Chengchen Deng,HongYan Xue,Jiaojiao Zhang,Wenjing Yang,Xianzhong Wang
标识
DOI:10.1016/j.theriogenology.2023.11.027
摘要
Heat stress leads to the accumulation of lipid peroxides in Sertoli cells. Unrestricted lipid peroxidation of catalyzed polyunsaturated fatty acids by Cytochrome P450 (CYP) drive the ferroptosis. However, little is known about the role of CYP cyclooxygenase in heat stress-induced ferroptosis in Sertoli cells. In this study, we investigated the relationship between CYP cyclooxygenase and heat stress-induced ferroptosis in porcine Sertoli cells, as well as whether Ras-JNK signaling is involved in the process. The results showed that heat stress significantly increased the expression of cytochrome P450 cyclooxygenase 2C9 (CYP2C9) and the content of epoxyeicosatrienoic acids (EETs), although there are no significant effect on the expression of cytochrome P450 cyclooxygenase 2J2 (CYP2J2) and cytochrome P450 cyclooxygenase 2C8 (CYP2C8). In addition, heat stress reduced the cell viability, the protein expression level of glutathione peroxidase 4 (GPX4) and Ferritin (all P < 0.01) while increased the level of intracellular reactive oxygen species (ROS) and the protein level of Transferrin receptor 1(TFR1) (both P < 0.01), as well as activating the Ras-JNK signaling pathway. Ferrostatin-1, a ferroptosis-specific inhibitor, reduced ROS levels and the protein level of TFR1 (both P < 0.01), but elevated the cell viability, the protein level of GPX4, and Ferritin (all P < 0.01). Sulfaphenazole, a specific inhibitor of CYP2C9 or two small interfering RNAs targaring CYP2C9 enhanced the cell viability (all P < 0.01), while reduced the content of EETs (all P < 0.01) and inhibited the Ras-JNK signaling and ferroptosis under heat stress. Salirasib, a specific inhibitor of Ras, significantly elevated the cell viability, whereas reduced the level of intracellular ROS and inhibited the phosphorylation of JNK, and alleviated heat stress-induced ferroptosis in porcine Sertoli cells. Notably, there is no effect on the expression of CYP2C9 and the content of EETs. These results indicate that heat stress can induce ferroptosis in Sertoli cells by increasing the expression of CYP2C9 and the content of EETs, which in true activates the Ras-JNK signaling pathway, but there is no feedback from Ras-JNK signaling to the expression of CYP2C9. Our study finds a novel heat stress-induced cell death model of Sertoli cells as well as providing the therapeutic potential for anti-ferroptosis.
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