Jiang Shuang, Qiu Suhua, Mu Yu, Liu Chilu, Han Yanxing, Jiang Jiandong, Wang Yuhong
State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China.
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei Province, China.
Free Radic Biol Med. 2025 Feb 1;227:472-484. doi: 10.1016/j.freeradbiomed.2024.12.005. Epub 2024 Dec 6.
Obesity is a significant risk factor for cardiac arrhythmias, and the ferroptosis is closely related to cardiac arrhythmias. This study aimed to investigate whether puerarin (Pue), a natural isoflavone, could reduce the susceptibility to ventricular arrhythmias (VAs) associated with obesity and inhibit ferroptosis, with a particular focus on the Sirt1/Nrf2 signaling pathway. Male rats were randomly divided into three groups: normal chow diet (NC), high-fat diet (HFD), and HFD with Pue treatment (100mg/kg, HFD + Pue). After 16 weeks, electrophysiological, structural, and molecular analysis were performed. Compared to the NC group, HFD rats exhibited prolonged QT interval and Tpeak-Tend interval, amplified transmural dispersion of ventricular repolarization, and increased susceptibility to VAs. Pue treatment significantly ameliorated these electrophysiological abnormalities and reduced VAs susceptibility. HFD rats showed cardiac hypertrophy, fibrosis, and inflammation, which were alleviated by Pue application. Cardiac lipid peroxidation, iron deposition, mitochondrial abnormality, and ferroptosis marker induction were observed in HFD rats. Further, treatment with Pue improved these alterations. Additionally, molecular docking analysis confirmed the interaction of Pue with Sirt1 and Nrf2. Furthermore, Pue treatment upregulated Sirt1 and Nrf2 expression in HFD rats, thereby reducing reactive oxygen species (ROS) generation and ferroptosis. Moreover, Pue protected cardiomyocytes against palmitic acid (PA)-induced injury by inhibiting ferroptosis via the Sirt1/Nrf2 pathway in H9c2 cells. Overall, our study shows for the first time that Pue reduces susceptibility to VAs and inhibits ferroptosis in HFD rats by modulating the Sirt1/Nrf2 signaling pathway, offering a potential therapeutic strategy for obesity-related cardiac arrhythmias.
肥胖是心律失常的一个重要危险因素，而铁死亡与心律失常密切相关。本研究旨在探讨天然异黄酮葛根素（Pue）是否能降低肥胖相关室性心律失常（VAs）的易感性并抑制铁死亡，特别关注Sirt1/Nrf2信号通路。雄性大鼠随机分为三组：正常饮食（NC）组、高脂饮食（HFD）组和Pue治疗的高脂饮食组（100mg/kg，HFD + Pue）。16周后，进行电生理、结构和分子分析。与NC组相比，HFD大鼠QT间期和Tpeak-Tend间期延长，心室复极跨壁离散度增大，VAs易感性增加。Pue治疗显著改善了这些电生理异常并降低了VAs易感性。HFD大鼠表现出心脏肥大、纤维化和炎症，Pue应用可减轻这些症状。在HFD大鼠中观察到心脏脂质过氧化、铁沉积、线粒体异常和铁死亡标志物诱导。此外，Pue治疗改善了这些改变。另外，分子对接分析证实了Pue与Sirt1和Nrf2的相互作用。此外，Pue治疗上调了HFD大鼠中Sirt1和Nrf2的表达，从而减少活性氧（ROS）生成和铁死亡。此外，Pue通过抑制H9c2细胞中Sirt1/Nrf2途径的铁死亡来保护心肌细胞免受棕榈酸（PA）诱导的损伤。总体而言，我们的研究首次表明，Pue通过调节Sirt1/Nrf2信号通路降低HFD大鼠对VAs的易感性并抑制铁死亡，为肥胖相关心律失常提供了一种潜在的治疗策略。
