Formononetin attenuates myocardial ischemia/reperfusion injury by regulating neutrophil extracellular traps formation and platelet activation via platelet CD36

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-04-09 DOI:10.1016/j.phymed.2025.156736

Shuang Tang , Jing-xue Ye , Ruo-yun Li , Jia-lu Wang , Hao-chen Xie , Ya-qi Zhang , Min Wang , Gui-bo Sun

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引用次数: 0

Abstract

Background

Prothrombotic and proinflammatory responses are crucial in the pathology of myocardial ischemia-reperfusion injury (MIRI). Platelets and neutrophil extracellular traps (NETs) are essential to linking inflammation with thrombosis. Formononetin (FMN), an isoflavone extracted from Astragalus membranaceus, has anti-inflammatory and anti-thrombotic effects and confers benefits on MIRI. However, the mechanisms of FMN against MIRI remain unclear.

Purpose

This study explored FMN's roles and mechanisms in modulating platelet activation and NETs formation to mitigate MIRI.

Study design and methods

A rat model of MIRI by the left anterior descending coronary artery ligation was utilized to evaluate the role of FMN. 60 Sprague-Dawley male rats were randomly divided into 7 groups. Proteomics, flow cytometry, immunofluorescence, ELISA, and western blotting assays were performed to reveal the potential mechanisms of FMN. Neutrophils treated with platelet-rich plasma were applied to further explore the mechanisms of FMN in vitro.

Results

We showed that FMN administration declined myocardial infarct size and improved cardiac function. Moreover, FMN significantly reduced MIRI-induced platelet activation including platelet aggregation, platelet adhesion, platelet granule secretion, and platelet-leukocyte aggregation without affecting tail bleeding time. Additionally, FMN inhibited microthrombus, platelet-neutrophil aggregation, and NETs formation in myocardial tissue. Mechanistically, FMN attenuated MIRI-induced CD36 expression and phosphorylation of ERK5 in platelets. Furthermore, up-regulation of CD36 content in vitro counteracted the potency of FMN to inhibit platelet activation and NETs formation.

Conclusion

FMN mitigates thrombosis and inflammation in MIRI by inhibiting platelet activation and NETs formation via the CD36 pathway. This research offers important insights for future studies on MIRI prevention.

Abstract Image

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刺芒柄花素通过血小板CD36调节中性粒细胞胞外陷阱形成和血小板活化，减轻心肌缺血/再灌注损伤

背景：血栓形成前和促炎反应在心肌缺血再灌注损伤（MIRI）的病理过程中起着至关重要的作用。血小板和中性粒细胞胞外陷阱（NETs）是连接炎症与血栓形成的必要条件。刺芒柄花素（FMN）是一种从黄芪中提取的异黄酮，具有抗炎和抗血栓作用，对MIRI有益处。然而，FMN抗MIRI的机制尚不清楚。目的探讨FMN在调节血小板活化和NETs形成以减轻MIRI中的作用和机制。研究设计与方法采用冠状动脉左前降支结扎大鼠MIRI模型评价FMN的作用。选取60只雄性Sprague-Dawley大鼠随机分为7组。通过蛋白质组学、流式细胞术、免疫荧光、ELISA和western blotting检测揭示FMN的潜在机制。利用富血小板血浆处理的中性粒细胞进一步探讨体外FMN的作用机制。结果FMN可降低心肌梗死面积，改善心功能。此外，FMN显著降低了mri诱导的血小板活化，包括血小板聚集、血小板粘附、血小板颗粒分泌和血小板-白细胞聚集，而不影响尾出血时间。此外，FMN抑制心肌组织中的微血栓、血小板-中性粒细胞聚集和NETs形成。在机制上，FMN减弱了miri诱导的血小板中CD36的表达和ERK5的磷酸化。此外，体外CD36含量上调抵消了FMN抑制血小板活化和NETs形成的效力。结论fmn通过CD36途径抑制血小板活化和NETs形成，减轻MIRI血栓形成和炎症。该研究为未来MIRI预防研究提供了重要见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.