Yan Musan, Wang Yuewei, Niu Liyuan, Wang Shaoying, Yu Haichu, Yin Qikai, Zhang Dachuan, Bai Yunduo, Yin Yuanjie, Lin Shiping, Liu Chuanfeng, Zhang Mingxue, Tang Xiaopeng, Ni Heyu, Xue Min, Li Changjiang
School of Basic Medicine, Qingdao University, Qingdao, Shandong, China.
Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
J Thromb Haemost. 2025 Sep;23(9):2837-2848. doi: 10.1016/j.jtha.2025.05.033. Epub 2025 Jun 9.
Inflammation is crucial in regulating coagulation and hemostasis. While prior research shows that apolipoprotein A-IV (ApoA-IV) has anti-inflammatory and antiplatelet effects, its specific impact on coagulation remains unclear.
To investigate the effects of ApoA-IV on the coagulation system, including its interactions with potential targets and the underlying mechanisms.
Plasma ApoA-IV levels in deep vein thrombosis patients were tested by enzyme-linked immunosorbent assay. The effects of ApoA-IV on coagulation were assessed through thromboelastography. Potential interactions and mechanisms were analyzed using surface plasmon resonance and AlphaFold 3. Mice bleeding and stroke models were employed to evaluate the effects on hemostasis and thrombosis.
ApoA-IV levels were reduced in deep vein thrombosis patients and correlated with increased thrombotic risk. Thromboelastography showed that ApoA-IV treatment delayed clot reaction and kinetic times while decreasing thrombus generation angle and maximum amplitude, highlighting its crucial role in inhibiting coagulation and platelet aggregation. We identified ApoA-IV as a functional activator of activated protein C (APC), with critical interactions occurring at residues 144 to 148 within the exosite loop of the APC protease domain. In animal models, anti-ApoA-IV antibody administration shortened bleeding time but exacerbated ischemic stroke outcomes. Notably, inhibitory peptide HE5, which inhibits ApoA-IV-APC interaction, effectively counteracted the anticoagulant activity of ApoA-IV.
These findings establish ApoA-IV as a pivotal regulator of coagulation and hemostasis, primarily through enhancing APC activity. This research advances our understanding of the interplay between inflammation, lipid metabolism, and thrombosis, offering insights for developing novel antithrombotic therapies.
炎症在调节凝血和止血过程中起着关键作用。虽然先前的研究表明载脂蛋白A-IV（ApoA-IV）具有抗炎和抗血小板作用，但其对凝血的具体影响仍不清楚。
研究ApoA-IV对凝血系统的影响，包括其与潜在靶点的相互作用及潜在机制。
采用酶联免疫吸附测定法检测深静脉血栓形成患者的血浆ApoA-IV水平。通过血栓弹力图评估ApoA-IV对凝血的影响。使用表面等离子体共振和AlphaFold 3分析潜在的相互作用和机制。采用小鼠出血和中风模型评估对止血和血栓形成的影响。
深静脉血栓形成患者的ApoA-IV水平降低，且与血栓形成风险增加相关。血栓弹力图显示，ApoA-IV治疗可延迟凝血反应和动力学时间，同时减小血栓生成角度和最大振幅，突出了其在抑制凝血和血小板聚集方面的关键作用。我们确定ApoA-IV是活化蛋白C（APC）的功能性激活剂，关键相互作用发生在APC蛋白酶结构域外部位点环内的144至148位残基处。在动物模型中，给予抗ApoA-IV抗体可缩短出血时间，但会加重缺血性中风的后果。值得注意的是，抑制ApoA-IV与APC相互作用的抑制肽HE5有效抵消了ApoA-IV的抗凝活性。
这些发现确立了ApoA-IV作为凝血和止血的关键调节因子，主要是通过增强APC活性实现的。这项研究推进了我们对炎症、脂质代谢和血栓形成之间相互作用的理解，为开发新型抗血栓治疗方法提供了见解。
