Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Redox Biol. 2023 Sep;65:102825. doi: 10.1016/j.redox.2023.102825. Epub 2023 Jul 24.
Chemotherapeutic agents, such as doxorubicin (DOX), may cause cardiomyopathy, even life-threatening arrhythmias in cancer patients. Ferroptosis-an iron-dependent oxidative form of programmed necrosis, plays a pivotal role in DOX-induced cardiomyopathy (DIC). Prostaglandins (PGs) are bioactive signaling molecules that profoundly modulate cardiac performance in both physiologic and pathologic conditions. Here, we found that PGE production and its E-prostanoid 1 receptor (EP1) expression were upregulated in erastin (a ferroptosis inducer) or DOX-treated cardiomyocytes. EP1 inhibition markedly aggravated erastin or DOX-induced cardiomyocyte ferroptosis, whereas EP1 activation exerted opposite effect. Genetic depletion of EP1 in cardiomyocytes worsens DOX-induced cardiac injury in mice, which was efficiently rescued by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Mechanistically, EP1 activation protected cardiomyocytes from DOX-induced ferroptosis by promoting nuclear factor erythroid 2-related factor 2 (Nrf2)-driven anti-oxidative gene expression, such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). EP1 was coupled with G to elicit intracellular Ca flux and activate the PKC/Nrf2 cascade in ferroptotic cardiomyocytes. EP1 activation also prevents DOX-induced ferroptosis in human cardiomyocytes. Thus, PGE/EP1 axis protects cardiomyocytes from DOX-induced ferroptosis by activating PKC/Nrf2 signaling and activation of EP1 may represent an attractive strategy for DIC prevention and treatment.
化疗药物，如多柔比星（DOX），可能导致癌症患者的心肌病，甚至危及生命的心律失常。铁死亡——一种铁依赖性的程序性细胞坏死的氧化形式，在 DOX 诱导的心肌病（DIC）中起着关键作用。前列腺素（PGs）是生物活性信号分子，在生理和病理条件下深刻调节心脏功能。在这里，我们发现前列腺素 E 产生及其 E-前列腺素 1 受体（EP1）表达在 erastin（一种铁死亡诱导剂）或 DOX 处理的心肌细胞中上调。EP1 抑制显著加剧 erastin 或 DOX 诱导的心肌细胞铁死亡，而 EP1 激活则产生相反的效果。心肌细胞中 EP1 的基因缺失使小鼠的 DOX 诱导的心脏损伤恶化，而铁死亡抑制剂 Ferrostatin-1（Fer-1）则有效地挽救了这一情况。在机制上，EP1 激活通过促进核因子红细胞 2 相关因子 2（Nrf2）驱动的抗氧化基因表达，如谷胱甘肽过氧化物酶 4（GPX4）和溶质载体家族 7 成员 11（SLC7A11），保护心肌细胞免受 DOX 诱导的铁死亡。EP1 与 G 偶联以引起细胞内 Ca 流，并激活铁死亡心肌细胞中的 PKC/Nrf2 级联。EP1 激活还可防止人心肌细胞中 DOX 诱导的铁死亡。因此，PGE/EP1 轴通过激活 PKC/Nrf2 信号来保护心肌细胞免受 DOX 诱导的铁死亡，EP1 的激活可能代表预防和治疗 DIC 的一种有吸引力的策略。
