Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113394. doi: 10.1016/j.intimp.2024.113394. Epub 2024 Oct 21.
Ischemia/reperfusion (I/R) injury has been demonstrated to exert a significant role in acute myocardial infarction (AMI), which constitutes a crucial cause of AMI. Ferroptosis represents a novel form of cell death that is intimately linked to myocardial ischemia-reperfusion (MIR) injury. Urolithin A (UA), an intestinal metabolite of ellagitannins, has not been fully elucidated for its role in MIR injury. In the present study, we analyzed the effects of UA on ischemia-reperfusion-induced oxidative stress and ferroptosis both in vitro and in vivo, and explored the potential mechanisms of UA action. The results indicated that UA was capable of protecting the heart from ischemia-reperfusion injury and enhancing cardiac function both in vitro and in vivo. In addition, UA also attenuated oxidative stress, mitochondrial damage, and ferroptosis during MIR. Mechanistically, UA not only augmented the Nrf2 expression but also promoted Nrf2 entry into the nucleus and activated the downstream antioxidant defense system. Moreover, after the inhibition of Nrf2, the myocardial protective function of UA was lost, and its function of attenuating oxidative stress and ferroptosis was suppressed. In conclusion, we found that UA protected the heart from ischemia-reperfusion injury by attenuating oxidative stress and ferroptosis through the Nrf2 signaling pathway, suggesting that UA might be a potential therapeutic agent for the treatment of AMI.
缺血再灌注 (I/R) 损伤已被证明在急性心肌梗死 (AMI) 中发挥重要作用，是 AMI 的重要原因。铁死亡是一种新的细胞死亡形式，与心肌缺血再灌注 (MIR) 损伤密切相关。鞣花单宁的肠道代谢物尿石素 A (UA) 尚未充分阐明其在 MIR 损伤中的作用。本研究分析了 UA 在体外和体内对缺血再灌注诱导的氧化应激和铁死亡的影响，并探讨了 UA 作用的潜在机制。结果表明，UA 能够保护心脏免受缺血再灌注损伤，并增强体外和体内的心脏功能。此外，UA 还减轻了 MIR 期间的氧化应激、线粒体损伤和铁死亡。在机制上，UA 不仅增强了 Nrf2 的表达，还促进了 Nrf2 进入细胞核并激活了下游抗氧化防御系统。此外，抑制 Nrf2 后，UA 的心肌保护功能丧失，其减轻氧化应激和铁死亡的功能受到抑制。总之，我们发现 UA 通过 Nrf2 信号通路减轻氧化应激和铁死亡来保护心脏免受缺血再灌注损伤，提示 UA 可能是治疗 AMI 的潜在治疗药物。
