Perfluoroalkyl and polyfluoroalkyl substances interact with platelet glycoprotein Ibα and exacerbate thrombosis

IF 12.2 1区环境科学与生态学 Q1 ENGINEERING, ENVIRONMENTAL

Journal of Hazardous Materials Pub Date : 2025-05-05 DOI:10.1016/j.jhazmat.2025.138506

Ming Liu, Weiqing Zhao, Chaoyu Ma, Muhammad Awais, Xue Chen, Yiting Feng, Tianyu Wang, Shaoyun Zhou, Yan Bai, Shuai Jiang, Dachuan Zhang, Guangheng Zhu, Xiaohong Ruby Xu, Miao Xu, Heyu Ni, Chuanbin Shen

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Abstract

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are highly stable man-made chemicals. They have recently garnered significant attention due to their ubiquitous presence in the environment and deleterious effects on human health including cardiovascular diseases (CVDs). Thrombosis due to platelet activation is a major aspect in CVDs. However, the direct effect and underlying mechanism of PFAS on the platelets remains elusive. Here, we observed that PFAS engagement with the extracellular domain of platelet GPIbα, transduced GPIbα-driven inward signals, resulting in intracellular calcium mobilization, activation of AKT and αⅡbβ3 integrin, culminating in platelet aggregation and procoagulant platelet formation. PFAS pretreatment enhanced GPIb-mediated platelet spreading and thrombus formation under high shear conditions. PFAS-induced platelet activation was markedly decreased in Gpibα-deficient mice. PFAS-primed platelets drove neutrophil extracellular traps formation through GPIbα-dependent pathway. Further, PFAS-exposed mice showed heightened risk of thrombus growth and ischemic stroke. Our findings provide experimental evidence for the causal links between PFAS exposure and thrombotic CVDs. Blockade of GPIbα and the downstream pathways could be an instrumental strategy against PFAS-induced platelet activation and thrombosis.

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全氟烷基和多氟烷基物质与血小板糖蛋白Ibα相互作用，加重血栓形成

全氟烷基和多氟烷基物质（PFAS）是高度稳定的人造化学品。由于它们在环境中无处不在以及对包括心血管疾病（cvd）在内的人类健康的有害影响，它们最近引起了极大的关注。血小板活化引起的血栓形成是心血管疾病的一个主要方面。然而，PFAS对血小板的直接作用和潜在机制尚不清楚。在这里，我们观察到PFAS与血小板GPIbα的细胞外结构域结合，转导GPIbα驱动的内向信号，导致细胞内钙动员，激活AKT和αⅡbβ3整合素，最终导致血小板聚集和促凝血小板形成。在高剪切条件下，PFAS预处理增强了gpib介导的血小板扩散和血栓形成。pfas诱导的血小板活化在gpib α-缺陷小鼠中明显降低。pfas引物血小板通过gpib α依赖途径驱动中性粒细胞胞外陷阱的形成。此外，暴露于pfas的小鼠显示血栓生长和缺血性中风的风险增加。我们的研究结果为PFAS暴露与血栓性cvd之间的因果关系提供了实验证据。阻断GPIbα及其下游通路可能是对抗pfas诱导的血小板活化和血栓形成的有效策略。

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来源期刊

Journal of Hazardous Materials 工程技术-工程：环境

CiteScore

25.40

自引率

5.90%

发文量

3059

审稿时长

58 days

期刊介绍： The Journal of Hazardous Materials serves as a global platform for promoting cutting-edge research in the field of Environmental Science and Engineering. Our publication features a wide range of articles, including full-length research papers, review articles, and perspectives, with the aim of enhancing our understanding of the dangers and risks associated with various materials concerning public health and the environment. It is important to note that the term "environmental contaminants" refers specifically to substances that pose hazardous effects through contamination, while excluding those that do not have such impacts on the environment or human health. Moreover, we emphasize the distinction between wastes and hazardous materials in order to provide further clarity on the scope of the journal. We have a keen interest in exploring specific compounds and microbial agents that have adverse effects on the environment.