Ma Jiaxin, Wang Yaheng, Lv Huijiao, Lei Yu, Guan Feifei, Dong Wei, Wang He, Zhang Lianfeng, Lu Dan
National Center of Technology Innovation for Animal Model, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing, China.
National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing, China.
Cell Commun Signal. 2025 Apr 30;23(1):208. doi: 10.1186/s12964-025-02197-w.
Cytochrome P450 2E1 (CYP2E1), a drug metabolism enzyme, is linked to multiple pathophysiological states in the myocardium and may act as a sensor of heart diseases. However, the exact mechanisms of CYP2E1 in myocardial injury, particularly in chemotherapeutic agent-induced myocardial damage such as doxorubicin-induced cardiotoxicity, remain unclear.
Using multiple animal models of cardiomyopathy and heart failure, we observed CYP2E1 expression in myocardial mitochondria. Myocardium-specific CYP2E1 overexpression and knockout rat models were employed to study its effects on myocardial injury, assessed via echocardiography and histopathology. Mechanistic insights were derived from transcriptome analysis, mass spectrometry, co-immunoprecipitation, signal transduction analysis, and molecular biology techniques.
CYP2E1 overexpression accelerated, while CYP2E1 knockout inhibited, myocardial injury in DXR-induced cardiomyopathy and isoprenaline-induced hypertrophic cardiomyopathy. Mechanistically, CYP2E1 was upregulated specifically in myocardial mitochondria during heart disease. This upregulation resulted in mitochondrial fragmentation and dysfunction under DXR-induced stress. CYP2E1 interacted with optic atrophy 1 (OPA1) in the inner mitochondrial membrane, leading to an imbalance between long and short OPA1 isoforms.
CYP2E1 disrupts OPA1-mediated mitochondrial dynamics, causing mitochondrial fragmentation and apoptosis, which aggravate myocardial injury. Targeting CYP2E1 may offer a therapeutic strategy to mitigate myocardial damage, particularly in chemotherapeutic drug-induced cardiotoxicity.
细胞色素P450 2E1（CYP2E1）是一种药物代谢酶，与心肌中的多种病理生理状态相关，可能作为心脏病的一种传感器。然而，CYP2E1在心肌损伤中的具体机制，尤其是在化疗药物诱导的心肌损伤（如阿霉素诱导的心脏毒性）中，仍不清楚。
我们使用多种心肌病和心力衰竭动物模型，观察心肌线粒体中CYP2E1的表达。采用心肌特异性CYP2E1过表达和敲除大鼠模型，通过超声心动图和组织病理学评估其对心肌损伤的影响。通过转录组分析、质谱分析、免疫共沉淀、信号转导分析和分子生物学技术深入了解其机制。
在阿霉素诱导的心肌病和异丙肾上腺素诱导的肥厚性心肌病中，CYP2E1过表达加速了心肌损伤，而CYP2E1敲除则抑制了心肌损伤。机制上，在心脏病期间，CYP2E1在心肌线粒体中特异性上调。这种上调导致在阿霉素诱导的应激下线粒体碎片化和功能障碍。CYP2E1在线粒体内膜与视神经萎缩蛋白1（OPA1）相互作用，导致长、短OPA1异构体之间失衡。
CYP2E1破坏OPA1介导的线粒体动力学，导致线粒体碎片化和细胞凋亡，加重心肌损伤。靶向CYP2E1可能为减轻心肌损伤提供一种治疗策略，尤其是在化疗药物诱导的心脏毒性方面。
