Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China.
Department of General Practice, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China.
Phytother Res. 2024 Nov;38(11):5290-5308. doi: 10.1002/ptr.8315. Epub 2024 Sep 3.
Reperfusion therapy is the primary treatment strategy for acute myocardial infarction (AMI). Paradoxically, it can lead to myocardial damage, namely myocardial ischemia/reperfusion injury (MIRI). This study explored whether oroxylin A (OA) protects the myocardium after MIRI by inhibiting ferroptosis and the underlying mechanism. In vivo, we established an MIRI model to investigate the protective effect of OA. In vitro, H9C2 cells were used to explore the regulation of ferroptosis by OA through immunofluorescence staining, western blotting, assay kits, etc. Additionally, RNA sequencing analysis (RNA-seq) and network pharmacology analyses were conducted to elucidate the molecular mechanisms. Our results showed that MIRI caused cardiac structural and functional damage in rats. MIRI promoted ferroptosis, which was consistently observed in vitro. However, pretreatment with OA reversed these effects. The mitogen-activated protein kinases (MAPK) signaling pathway participated in the MIRI process, with dual-specificity phosphatase 10 (DUSP10) found to regulate it. Further confirmation was provided by knocking down DUSP10 using small interfering RNA (siRNA), demonstrating the activation of the DUSP10/MAPK-Nrf2 pathway by OA to protect H9C2 cells from ferroptosis. Our research has demonstrated the mitigating effect of OA on MIRI and the improvement of myocardial function for the first time. The inhibition of ferroptosis has been identified as one of the mechanisms through which OA exerts its myocardial protective effects. Moreover, we have first unveiled that DUSP10 serves as an upstream target involved in mediating ferroptosis, and the regulation of the DUSP10/MAPK-Nrf2 pathway by OA is crucial in inhibiting ferroptosis to protect the myocardium.
再灌注治疗是急性心肌梗死（AMI）的主要治疗策略。矛盾的是，它会导致心肌损伤，即心肌缺血/再灌注损伤（MIRI）。本研究探讨了奥罗西林 A（OA）是否通过抑制铁死亡来保护 MIRI 后的心肌及其潜在机制。在体内，我们建立了 MIRI 模型来研究 OA 的保护作用。在体外，使用 H9C2 细胞通过免疫荧光染色、western blot 分析、试剂盒等方法来探讨 OA 对铁死亡的调控。此外，还进行了 RNA 测序分析（RNA-seq）和网络药理学分析以阐明分子机制。我们的结果表明，MIRI 导致大鼠心脏结构和功能损伤。MIRI 促进了铁死亡，这在体外也得到了一致的观察。然而，OA 的预处理逆转了这些效应。丝裂原活化蛋白激酶（MAPK）信号通路参与了 MIRI 过程，发现双特异性磷酸酶 10（DUSP10）调节该通路。使用小干扰 RNA（siRNA）敲低 DUSP10 进一步证实了 OA 通过激活 DUSP10/MAPK-Nrf2 通路来保护 H9C2 细胞免受铁死亡的作用。本研究首次证明了 OA 对 MIRI 的缓解作用及其对心肌功能的改善作用。抑制铁死亡被确定为 OA 发挥心肌保护作用的机制之一。此外，我们首次揭示了 DUSP10 作为参与介导铁死亡的上游靶点，OA 对 DUSP10/MAPK-Nrf2 通路的调节对于抑制铁死亡以保护心肌至关重要。
