Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Formononetin attenuates myocardial ischemia/reperfusion injury by regulating neutrophil extracellular traps formation and platelet activation via platelet CD36.
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Tang Shuang, Ye Jing-Xue, Li Ruo-Yun, Wang Jia-Lu, Xie Hao-Chen, Zhang Ya-Qi, Wang Min, Sun Gui-Bo
Аннотация
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.
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.