Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, China; Cardiovascular Research Institute of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China.
Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, China; Cardiovascular Research Institute of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China.
Eur J Pharmacol. 2021 Dec 15;913:174622. doi: 10.1016/j.ejphar.2021.174622. Epub 2021 Nov 5.
Sepsis is a known risk factor for new-onset atrial fibrillation (AF), and previous studies have demonstrated that ferroptosis participates in sepsis-induced organ injury development. Nevertheless, the role of ferroptosis in new-onset AF with sepsis remains largely unknown. This study aims to investigate the underlying mechanisms linking ferroptosis and AF caused by sepsis. LPS-induced endotoxemia is often used to model the acute inflammatory response associated with sepsis. Herein, we reported that ferroptosis was significantly activated in LPS-induced endotoxemia rat model. We also observed that ferroportin (Fpn), the only identified mammalian non-heme iron exporter, was downregulated in the atrium of endotoxemia model. Vulnerability to AF was also significantly increased in a endotoxemia rat model. Additionally, Fpn knockdown by shFpn further increased intracellular iron concentration and oxidative stress and exaggerated the AF vulnerability, which was alleviated by ferroptosis inhibition. Mechanistically, silencing Fpn worsened the alterations in calcium handling proteins expression in a endotoxemia rat model. These findings suggest that Fpn-mediated ferroptosis is involved in the new-onset AF with LPS-induced endotoxemia via worsening the calcium handling proteins dysregulation and provides a novel and promising strategy for preventing AF development in sepsis.
脓毒症是新发心房颤动（AF）的已知危险因素，先前的研究表明铁死亡参与了脓毒症引起的器官损伤发展。然而，铁死亡在脓毒症引起的新发 AF 中的作用在很大程度上仍不清楚。本研究旨在探讨铁死亡与脓毒症引起的 AF 之间的潜在机制。脂多糖（LPS）诱导的内毒素血症常被用于模拟与脓毒症相关的急性炎症反应。在此，我们报道铁死亡在 LPS 诱导的内毒素血症大鼠模型中明显被激活。我们还观察到，铁蛋白（Fpn），唯一鉴定出的哺乳动物非血红素铁输出蛋白，在内毒素血症模型的心房中被下调。内毒素血症大鼠模型的 AF 易感性也显著增加。此外，shFpn 敲低 Fpn 进一步增加了细胞内铁浓度和氧化应激，并加剧了 AF 易感性，而铁死亡抑制可减轻这种易感性。机制上，沉默 Fpn 在内毒素血症大鼠模型中加重了钙处理蛋白表达的改变。这些发现表明，Fpn 介导的铁死亡通过加重钙处理蛋白失调参与了 LPS 诱导的内毒素血症所致的新发 AF，并为预防脓毒症中 AF 的发展提供了一种新的有前途的策略。
