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

IF 7.4 1区 医学 Q1 HEMATOLOGY Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2024-07-01 Epub Date: 2024-05-16 DOI:10.1161/ATVBAHA.124.320899
Rida A Malik, Ji Zhou, James C Fredenburgh, Jeff Crosby, Alexey S Revenko, Jeff S Healey, Jeffrey I Weitz
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引用次数: 0

摘要

背景:聚磷酸盐(polyP)是一种从血小板释放的促凝血剂,可通过接触系统激活凝血,并调节心肌细胞的活力。大剂量静脉注射 polyP 会导致小鼠死亡,原因可能是血栓形成。此前,我们发现 HRG(富含组氨酸的糖蛋白)可结合 polyP 并减弱其促凝作用。在这项研究中,我们探讨了导致小鼠静脉注射 polyP 致死的机制以及 HRG 对这一过程的影响:方法:比较野生型小鼠和 HRG 缺陷小鼠静脉注射合成或血小板衍生 polyP(剂量高达 50 毫克/千克)或生理盐水后的存活率。为了确定血栓形成的作用,研究人员检测了 FXII(因子 XII)基因敲除或依诺肝素对 polyP 诱导的肺部纤维蛋白沉积的影响。为了评估心脏毒性,对心电图进行了连续监测,对肌钙蛋白 I 和肌酸激酶心肌带的水平进行了量化,并测定了在没有或有 HRG 的情况下暴露于 polyP 的小鼠心肌细胞系的存活率:结果:在缺乏 HRG 的小鼠中,30 毫克/千克的 polyP 即可致死,而在野生型小鼠中,50 毫克/千克的 polyP 即可致死。虽然 FXII 基因敲除或服用依诺肝素可减轻 polyP 诱导的肺部纤维蛋白沉积,但都不会影响死亡率。PolyP 可诱导剂量依赖性心电图异常,包括心脏传导阻滞和 ST 段改变,并增加肌钙蛋白和肌酸激酶心肌带的水平。与心脏毒性一致的是,多聚磷会以剂量依赖的方式降低培养的心肌细胞的活力,而补充 HRG 后这种效应会减弱:结论:大剂量静脉注射 polyP 对小鼠具有心脏毒性,而 HRG 可调节这种效应。
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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.

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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
337
审稿时长
2-4 weeks
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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