Rida A Malik, Ji Zhou, James C Fredenburgh, Jeff Crosby, Alexey S Revenko, Jeff S Healey, Jeffrey I Weitz
{"title":"富组氨酸糖蛋白可调节小鼠体内大剂量多磷酸盐的毒性效应","authors":"Rida A Malik, Ji Zhou, James C Fredenburgh, Jeff Crosby, Alexey S Revenko, Jeff S Healey, Jeffrey I Weitz","doi":"10.1161/ATVBAHA.124.320899","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Polyphosphate (polyP), a procoagulant released from platelets, activates coagulation via the contact system and modulates cardiomyocyte viability. High-dose intravenous polyP is lethal in mice, presumably because of thrombosis. Previously, we showed that HRG (histidine-rich glycoprotein) binds polyP and attenuates its procoagulant effects. In this study, we investigated the mechanisms responsible for the lethality of intravenous polyP in mice and the impact of HRG on this process.</p><p><strong>Methods: </strong>The survival of wild-type or HRG-deficient mice given intravenous synthetic or platelet-derived polyP in doses up to 50 mg/kg or saline was compared. To determine the contribution of thrombosis, the effect of FXII (factor XII) knockdown or enoxaparin on polyP-induced fibrin deposition in the lungs was examined. To assess cardiotoxicity, the ECG was continuously monitored, the levels of troponin I and the myocardial band of creatine kinase were quantified, and the viability of a cultured murine cardiomyocyte cell line exposed to polyP in the absence or presence of HRG was determined.</p><p><strong>Results: </strong>In HRG-deficient mice, polyP was lethal at 30 mg/kg, whereas it was lethal in wild-type mice at 50 mg/kg. Although FXII knockdown or enoxaparin administration attenuated polyP-induced fibrin deposition in the lungs, neither affected mortality. PolyP induced dose-dependent ECG abnormalities, including heart block and ST-segment changes, and increased the levels of troponin and myocardial band of creatine kinase, effects that were more pronounced in HRG-deficient mice than in wild-type mice and were attenuated when HRG-deficient mice were given supplemental HRG. Consistent with its cardiotoxicity, polyP reduced the viability of cultured cardiomyocytes in a dose-dependent manner, an effect attenuated with supplemental HRG.</p><p><strong>Conclusions: </strong>High-dose intravenous polyP is cardiotoxic in mice, and HRG modulates this effect.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Histidine-Rich Glycoprotein Modulates the Toxic Effects of High-Dose Polyphosphate in Mice.\",\"authors\":\"Rida A Malik, Ji Zhou, James C Fredenburgh, Jeff Crosby, Alexey S Revenko, Jeff S Healey, Jeffrey I Weitz\",\"doi\":\"10.1161/ATVBAHA.124.320899\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Polyphosphate (polyP), a procoagulant released from platelets, activates coagulation via the contact system and modulates cardiomyocyte viability. High-dose intravenous polyP is lethal in mice, presumably because of thrombosis. Previously, we showed that HRG (histidine-rich glycoprotein) binds polyP and attenuates its procoagulant effects. In this study, we investigated the mechanisms responsible for the lethality of intravenous polyP in mice and the impact of HRG on this process.</p><p><strong>Methods: </strong>The survival of wild-type or HRG-deficient mice given intravenous synthetic or platelet-derived polyP in doses up to 50 mg/kg or saline was compared. To determine the contribution of thrombosis, the effect of FXII (factor XII) knockdown or enoxaparin on polyP-induced fibrin deposition in the lungs was examined. To assess cardiotoxicity, the ECG was continuously monitored, the levels of troponin I and the myocardial band of creatine kinase were quantified, and the viability of a cultured murine cardiomyocyte cell line exposed to polyP in the absence or presence of HRG was determined.</p><p><strong>Results: </strong>In HRG-deficient mice, polyP was lethal at 30 mg/kg, whereas it was lethal in wild-type mice at 50 mg/kg. Although FXII knockdown or enoxaparin administration attenuated polyP-induced fibrin deposition in the lungs, neither affected mortality. PolyP induced dose-dependent ECG abnormalities, including heart block and ST-segment changes, and increased the levels of troponin and myocardial band of creatine kinase, effects that were more pronounced in HRG-deficient mice than in wild-type mice and were attenuated when HRG-deficient mice were given supplemental HRG. Consistent with its cardiotoxicity, polyP reduced the viability of cultured cardiomyocytes in a dose-dependent manner, an effect attenuated with supplemental HRG.</p><p><strong>Conclusions: </strong>High-dose intravenous polyP is cardiotoxic in mice, and HRG modulates this effect.</p>\",\"PeriodicalId\":8401,\"journal\":{\"name\":\"Arteriosclerosis, Thrombosis, and Vascular Biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.4000,\"publicationDate\":\"2024-07-01\",\"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.124.320899\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/5/16 0:00:00\",\"PubModel\":\"Epub\",\"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.124.320899","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/5/16 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Histidine-Rich Glycoprotein Modulates the Toxic Effects of High-Dose Polyphosphate in Mice.
Background: Polyphosphate (polyP), a procoagulant released from platelets, activates coagulation via the contact system and modulates cardiomyocyte viability. High-dose intravenous polyP is lethal in mice, presumably because of thrombosis. Previously, we showed that HRG (histidine-rich glycoprotein) binds polyP and attenuates its procoagulant effects. In this study, we investigated the mechanisms responsible for the lethality of intravenous polyP in mice and the impact of HRG on this process.
Methods: The survival of wild-type or HRG-deficient mice given intravenous synthetic or platelet-derived polyP in doses up to 50 mg/kg or saline was compared. To determine the contribution of thrombosis, the effect of FXII (factor XII) knockdown or enoxaparin on polyP-induced fibrin deposition in the lungs was examined. To assess cardiotoxicity, the ECG was continuously monitored, the levels of troponin I and the myocardial band of creatine kinase were quantified, and the viability of a cultured murine cardiomyocyte cell line exposed to polyP in the absence or presence of HRG was determined.
Results: In HRG-deficient mice, polyP was lethal at 30 mg/kg, whereas it was lethal in wild-type mice at 50 mg/kg. Although FXII knockdown or enoxaparin administration attenuated polyP-induced fibrin deposition in the lungs, neither affected mortality. PolyP induced dose-dependent ECG abnormalities, including heart block and ST-segment changes, and increased the levels of troponin and myocardial band of creatine kinase, effects that were more pronounced in HRG-deficient mice than in wild-type mice and were attenuated when HRG-deficient mice were given supplemental HRG. Consistent with its cardiotoxicity, polyP reduced the viability of cultured cardiomyocytes in a dose-dependent manner, an effect attenuated with supplemental HRG.
Conclusions: High-dose intravenous polyP is cardiotoxic in mice, and HRG modulates this effect.
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.