通过EP1激活,可以通过Nrf2抑制多克索鲁比-心肌细胞铁
Bei Wang1, Yuxuan Jin2, Jiao Liu1
1Department 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.
Redox biology
|August 2, 2023
概括
前列腺素E2 (PGE2) 和它的受体EP1保护心脏细胞免受化疗诱导的铁亡. 激活EP1可能为预防或治疗多克索鲁比诱导的心肌病症提供了一个新的策略.
科学领域:
- 心血管生物学 心血管生物学
- 分子医学是分子医学.
- 在瘤学瘤学.
背景情况:
- 化疗,像多克索鲁比辛 (DOX) 一样,可以诱导心脏毒性,包括心肌病和心律失常.
- 铁,一种依赖于铁的细胞死亡形式,是DOX诱导心肌病 (DIC) 的关键机制.
- 前列腺素 (PGs) 是信号分子,在健康和疾病中影响心脏功能.
研究的目的:
- 调查普拉斯塔格兰丁E2 (PGE2) 和其受体E-prostanoid 1 (EP1) 在多克索鲁比诱导的铁亡中的作用.
- 阐明PGE2/EP1轴对DOX诱导心脏毒性的保护机制.
- 评估EP1激活作为DIC的潜在治疗策略.
主要方法:
- 用铁亡诱导剂 (erastin) 或DOX治疗心肌细胞,并调节EP1表达/活性.
- 在小鼠和体外人类心肌细胞模型中利用了EP1的遗传枯竭.
- 评估了铁亡标志物,心脏损伤和下游信号通路,包括Nrf2和抗氧化剂基因表达 (GPX4,SLC7A11).
主要成果:
- 在DOX治疗心肌细胞中,PGE2和EP1的表达被上调.
- 在小鼠中,EP1抑制加剧了铁亡,而EP1激活保护了DOX诱导的心肌细胞铁亡和心脏损伤.
- 通过通过Gαq/Ca2+/PKC级联来增强Nrf2驱动的抗氧化基因表达,EP1激活保护了心肌细胞.
结论:
- PGE2/EP1信号轴提供了对心肌细胞中DOX诱导的铁亡的保护.
- EP1的激活促进了Nrf2介导的抗氧化剂防御,减轻了铁亡和心脏损伤.
- 向EP1受体为预防和治疗多克索鲁比诱导的心肌病症提供了一个有前途的治疗途径.
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