{"title":"Oroxylin A reverses SHP-2 oxidative inactivation in GPVI signaling to suppress platelet activation and thrombus formation.","authors":"Yufei Chen, Yuan Lin, Jin Hong, Jiaorui Wang, Biling Li, Zixian Liu, Yongbo Ma, Xiaolan Sun, Shufang Wang, Mingjie Li, Meiling Wu, Deyu Fu, Jian Li, Mingzhu Wang, Liang Hu","doi":"10.1186/s12959-025-00709-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Arterial thrombotic events are the leading causes of death worldwide, and the therapeutic effects of current antiplatelet drugs are not fully satisfactory. Oroxylin A (OroA), a flavone compound extracted from Scutellaria radix, possesses cardioprotective and many other pharmacological effects. While platelets play a crucial role in the development of myocardial infarction, the direct effects of OroA on platelet activation and thrombosis have yet to be investigated.</p><p><strong>Methods: </strong>FeCl₃-induced arteriole thrombosis and whole-blood perfusion were used to assess the inhibitory effect of OroA on thrombus formation. A myocardial ischemia model was employed to evaluate the protective effect of OroA on myocardial injury. Multiple platelet function studies including platelet aggregation, platelet spreading, clot retraction were performed. Network pharmacology, flow cytometry, enzyme-linked immunosorbent assay, co-immunoprecipitation and western blot were utilized to explore the mechanism of OroA on platelet activation.</p><p><strong>Results: </strong>OroA inhibited thrombus formation with less bleeding risk compared with aspirin. OroA protected against myocardial injury by suppressing microvascular thrombosis and platelet infiltration. OroA suppressed different agonist-induced platelet activation in a concentration-dependent manner, showing greater antiplatelet activity against collagen-induced platelet aggregation compared to ADP or thrombin-induced aggregation. OroA decreased granule release, integrin αIIbβ3 activation, platelet spreading and clot retraction. As a flavone, OroA boosted superoxide dismutase (SOD) and glutathione (GSH) activities and decreased malondialdehyde (MDA), oxidized glutathione (GSSG) and ROS levels in platelets during oxidative stress. OroA binds to SHP-2 and prevents its oxidative inactivation, leading to the tyrosine dephosphorylation of Src, Syk and PLCγ2, as well as the reduction of Ca<sup>2+</sup> influx and PKC phosphorylation in GPVI signaling.</p><p><strong>Conclusions: </strong>OroA inhibits platelet activation, thrombus formation and myocardial injury via reversing SHP-2 oxidative inactivation thereby attenuating collagen-induced GPVI signaling. With minor bleeding risk and no obvious pharmacological toxicity, OroA holds promising therapeutic potential as an antithrombotic drug.</p>","PeriodicalId":22982,"journal":{"name":"Thrombosis Journal","volume":"23 1","pages":"26"},"PeriodicalIF":2.6000,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921655/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Thrombosis Journal","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12959-025-00709-9","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Arterial thrombotic events are the leading causes of death worldwide, and the therapeutic effects of current antiplatelet drugs are not fully satisfactory. Oroxylin A (OroA), a flavone compound extracted from Scutellaria radix, possesses cardioprotective and many other pharmacological effects. While platelets play a crucial role in the development of myocardial infarction, the direct effects of OroA on platelet activation and thrombosis have yet to be investigated.
Methods: FeCl₃-induced arteriole thrombosis and whole-blood perfusion were used to assess the inhibitory effect of OroA on thrombus formation. A myocardial ischemia model was employed to evaluate the protective effect of OroA on myocardial injury. Multiple platelet function studies including platelet aggregation, platelet spreading, clot retraction were performed. Network pharmacology, flow cytometry, enzyme-linked immunosorbent assay, co-immunoprecipitation and western blot were utilized to explore the mechanism of OroA on platelet activation.
Results: OroA inhibited thrombus formation with less bleeding risk compared with aspirin. OroA protected against myocardial injury by suppressing microvascular thrombosis and platelet infiltration. OroA suppressed different agonist-induced platelet activation in a concentration-dependent manner, showing greater antiplatelet activity against collagen-induced platelet aggregation compared to ADP or thrombin-induced aggregation. OroA decreased granule release, integrin αIIbβ3 activation, platelet spreading and clot retraction. As a flavone, OroA boosted superoxide dismutase (SOD) and glutathione (GSH) activities and decreased malondialdehyde (MDA), oxidized glutathione (GSSG) and ROS levels in platelets during oxidative stress. OroA binds to SHP-2 and prevents its oxidative inactivation, leading to the tyrosine dephosphorylation of Src, Syk and PLCγ2, as well as the reduction of Ca2+ influx and PKC phosphorylation in GPVI signaling.
Conclusions: OroA inhibits platelet activation, thrombus formation and myocardial injury via reversing SHP-2 oxidative inactivation thereby attenuating collagen-induced GPVI signaling. With minor bleeding risk and no obvious pharmacological toxicity, OroA holds promising therapeutic potential as an antithrombotic drug.
期刊介绍：
Thrombosis Journal is an open-access journal that publishes original articles on aspects of clinical and basic research, new methodology, case reports and reviews in the areas of thrombosis.
Topics of particular interest include the diagnosis of arterial and venous thrombosis, new antithrombotic treatments, new developments in the understanding, diagnosis and treatments of atherosclerotic vessel disease, relations between haemostasis and vascular disease, hypertension, diabetes, immunology and obesity.
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