{"title":"bad -葡萄糖激酶轴调控血小板活化和血栓形成。","authors":"Mengnan Yang, Shuang Chen, Qing Li, Kangxi Zhou, Yu Li, Chenglin Sun, Yue Xia, Jing Tan, Qiuxia Huang, Yuxin Jin, Renping Hu, Changgeng Ruan, Kesheng Dai, Rong Yan","doi":"10.1161/ATVBAHA.124.321738","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>BAD (Bcl2-associated death promoter), a member of the Bcl2 proapoptotic family, promotes cell apoptosis by sequestering the prosurvival proteins Bcl-XL and Bcl2 from the proapoptotic proteins BAK and BAX in nucleated cells. BAD is also expressed in platelets, playing a role in regulating platelet lifespan, apoptosis, and clearance. However, whether BAD regulates platelet activation and arterial thrombosis remains unclear.</p><p><strong>Methods: </strong>The role of BAD in platelet activation and arterial thrombosis was investigated using BAD-deficient mice (<i>Bad</i><sup><i>-/-</i></sup>), in vitro functional studies, and arterial thrombosis models. The regulatory effect of BAD on platelet energy metabolism was detected using a Seahorse Extracellular Flux Analyzer. The regulatory effect of BAD on glucokinase was investigated by coimmunoprecipitation and activity measurement. The glucokinase heterozygous knockout mice (<i>Gck</i><sup><i>+/-</i></sup>) and activator were used to study its role in platelet activation.</p><p><strong>Results: </strong>BAD-deficient mice (<i>Bad</i><sup><i>-/-</i></sup>) and wild-type mice transfused with <i>Bad</i><sup><i>-/-</i></sup> platelets displayed prolonged tail bleeding and arterial occlusion times. <i>Bad</i><sup><i>-/-</i></sup> platelets exhibited decreased aggregation in response to stimulations by proteinase-activated receptor 4-activating peptide, thrombin, and U46619. Furthermore, BAD ablation suppressed platelet integrin α<sub>IIb</sub>β<sub>3</sub> activation, granule secretion, and clot retraction induced by these agonists. Mechanistically, BAD interacted with glucokinase, and BAD deficiency resulted in decreased platelet glucokinase activity, mitochondrial oxidative phosphorylation, and mitochondrial ATP production. The partial loss of glucokinase (<i>Gck</i><sup><i>+/-</i></sup>) phenocopied platelet function defects caused by BAD deficiency, and a glucokinase activator rescued the impaired mitochondrial ATP production and function of <i>Bad</i><sup><i>-/-</i></sup> platelets. Additionally, the glucokinase activator enhanced human platelet activation.</p><p><strong>Conclusions: </strong>Our findings demonstrate the critical role of the BAD-glucokinase axis in platelet activation and thrombosis, suggesting a potential target for antithrombotic therapy.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4000,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"BAD-Glucokinase Axis Regulates Platelet Activation and Thrombosis.\",\"authors\":\"Mengnan Yang, Shuang Chen, Qing Li, Kangxi Zhou, Yu Li, Chenglin Sun, Yue Xia, Jing Tan, Qiuxia Huang, Yuxin Jin, Renping Hu, Changgeng Ruan, Kesheng Dai, Rong Yan\",\"doi\":\"10.1161/ATVBAHA.124.321738\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>BAD (Bcl2-associated death promoter), a member of the Bcl2 proapoptotic family, promotes cell apoptosis by sequestering the prosurvival proteins Bcl-XL and Bcl2 from the proapoptotic proteins BAK and BAX in nucleated cells. BAD is also expressed in platelets, playing a role in regulating platelet lifespan, apoptosis, and clearance. However, whether BAD regulates platelet activation and arterial thrombosis remains unclear.</p><p><strong>Methods: </strong>The role of BAD in platelet activation and arterial thrombosis was investigated using BAD-deficient mice (<i>Bad</i><sup><i>-/-</i></sup>), in vitro functional studies, and arterial thrombosis models. The regulatory effect of BAD on platelet energy metabolism was detected using a Seahorse Extracellular Flux Analyzer. The regulatory effect of BAD on glucokinase was investigated by coimmunoprecipitation and activity measurement. The glucokinase heterozygous knockout mice (<i>Gck</i><sup><i>+/-</i></sup>) and activator were used to study its role in platelet activation.</p><p><strong>Results: </strong>BAD-deficient mice (<i>Bad</i><sup><i>-/-</i></sup>) and wild-type mice transfused with <i>Bad</i><sup><i>-/-</i></sup> platelets displayed prolonged tail bleeding and arterial occlusion times. <i>Bad</i><sup><i>-/-</i></sup> platelets exhibited decreased aggregation in response to stimulations by proteinase-activated receptor 4-activating peptide, thrombin, and U46619. Furthermore, BAD ablation suppressed platelet integrin α<sub>IIb</sub>β<sub>3</sub> activation, granule secretion, and clot retraction induced by these agonists. Mechanistically, BAD interacted with glucokinase, and BAD deficiency resulted in decreased platelet glucokinase activity, mitochondrial oxidative phosphorylation, and mitochondrial ATP production. The partial loss of glucokinase (<i>Gck</i><sup><i>+/-</i></sup>) phenocopied platelet function defects caused by BAD deficiency, and a glucokinase activator rescued the impaired mitochondrial ATP production and function of <i>Bad</i><sup><i>-/-</i></sup> platelets. Additionally, the glucokinase activator enhanced human platelet activation.</p><p><strong>Conclusions: </strong>Our findings demonstrate the critical role of the BAD-glucokinase axis in platelet activation and thrombosis, suggesting a potential target for antithrombotic therapy.</p>\",\"PeriodicalId\":8401,\"journal\":{\"name\":\"Arteriosclerosis, Thrombosis, and Vascular Biology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":7.4000,\"publicationDate\":\"2025-03-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Arteriosclerosis, Thrombosis, and Vascular Biology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/ATVBAHA.124.321738\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arteriosclerosis, Thrombosis, and Vascular Biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/ATVBAHA.124.321738","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
BAD-Glucokinase Axis Regulates Platelet Activation and Thrombosis.
Background: BAD (Bcl2-associated death promoter), a member of the Bcl2 proapoptotic family, promotes cell apoptosis by sequestering the prosurvival proteins Bcl-XL and Bcl2 from the proapoptotic proteins BAK and BAX in nucleated cells. BAD is also expressed in platelets, playing a role in regulating platelet lifespan, apoptosis, and clearance. However, whether BAD regulates platelet activation and arterial thrombosis remains unclear.
Methods: The role of BAD in platelet activation and arterial thrombosis was investigated using BAD-deficient mice (Bad-/-), in vitro functional studies, and arterial thrombosis models. The regulatory effect of BAD on platelet energy metabolism was detected using a Seahorse Extracellular Flux Analyzer. The regulatory effect of BAD on glucokinase was investigated by coimmunoprecipitation and activity measurement. The glucokinase heterozygous knockout mice (Gck+/-) and activator were used to study its role in platelet activation.
Results: BAD-deficient mice (Bad-/-) and wild-type mice transfused with Bad-/- platelets displayed prolonged tail bleeding and arterial occlusion times. Bad-/- platelets exhibited decreased aggregation in response to stimulations by proteinase-activated receptor 4-activating peptide, thrombin, and U46619. Furthermore, BAD ablation suppressed platelet integrin αIIbβ3 activation, granule secretion, and clot retraction induced by these agonists. Mechanistically, BAD interacted with glucokinase, and BAD deficiency resulted in decreased platelet glucokinase activity, mitochondrial oxidative phosphorylation, and mitochondrial ATP production. The partial loss of glucokinase (Gck+/-) phenocopied platelet function defects caused by BAD deficiency, and a glucokinase activator rescued the impaired mitochondrial ATP production and function of Bad-/- platelets. Additionally, the glucokinase activator enhanced human platelet activation.
Conclusions: Our findings demonstrate the critical role of the BAD-glucokinase axis in platelet activation and thrombosis, suggesting a potential target for antithrombotic therapy.
期刊介绍：
The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA).
The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.
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