Maekawa Kazunari, Nakamura Eriko, Saito Yoichi, Matsuura Yunosuke, Gi Toshihiro, Nishihira Kensaku, Oguri Nobuyuki, Moriguchi-Goto Sayaka, Sato Yuichiro, Hatakeyama Kinta, Shibata Yoshisato, Komohara Yoshihiro, Kaikita Koichi, Asada Yujiro, Yamashita Atsushi
Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Miyazaki, Japan.
Bioengineering Lab, Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, Kumamoto, Japan.
PLoS One. 2025 Mar 4;20(3):e0316474. doi: 10.1371/journal.pone.0316474. eCollection 2025.
The thrombogenic potential of cells within atherosclerotic plaques is critical in the formation of a coronary thrombus. We hypothesized that a combination of inflammatory and hypoxic stimuli enhances tissue factor (TF) expression and glycolysis in cells in atherosclerotic plaques and contributes to coronary thrombus formation.
To identify TF- and hexokinase (HK)-II-expressing cells in coronary atherosclerotic plaques and thrombi and determine the effects of combined inflammatory and hypoxic stimuli and glycolysis on TF expression in peripheral blood mononuclear cell-derived macrophages.
We immunohistochemically assessed TF and HK-II expression in stable (n = 20) and unstable (n = 24) human coronary plaques and aspirated acute coronary thrombi (n = 15). The macrophages were stimulated with tumor necrosis factor-α, interferon-γ, or interleukin-10 under normoxic (21% O2) or hypoxic (1% O2) conditions, and TF expression was assessed.
TF and HK-II expression were increased in unstable plaques compared with stable plaques. The number of CD68- and HK-II-immunopositive cells positively correlated with the number of TF-immunopositive cells. TF- and HK-II-expressing macrophages, which expressed M1- or M2-like markers, were involved in platelet-fibrin thrombus formation in ruptured plaques. The combination of inflammatory and hypoxic conditions additively augmented TF expression and procoagulant activity in the cultured macrophages. Inhibition of glycolysis with 2-deoxyglucose reduced the augmented TF expression and procoagulant activity.
Combined inflammatory and hypoxic conditions in atherosclerotic plaques may markedly enhance procoagulant activity in macrophages and contribute to coronary thrombus formation following plaque disruption. Macrophage TF expression may be associated with glycolysis.
动脉粥样硬化斑块内细胞的致血栓形成潜能在冠状动脉血栓形成中起关键作用。我们推测炎症和缺氧刺激的联合作用会增强动脉粥样硬化斑块内细胞中组织因子（TF）的表达和糖酵解，并促进冠状动脉血栓形成。
鉴定冠状动脉粥样硬化斑块和血栓中表达TF和己糖激酶（HK）-II的细胞，并确定炎症和缺氧刺激及糖酵解联合作用对外周血单核细胞来源巨噬细胞中TF表达的影响。
我们采用免疫组织化学方法评估了20例稳定型和24例不稳定型人类冠状动脉斑块以及15例吸出的急性冠状动脉血栓中TF和HK-II的表达。在常氧（21% O₂）或缺氧（1% O₂）条件下，用肿瘤坏死因子-α、干扰素-γ或白细胞介素-10刺激巨噬细胞，并评估TF表达。
与稳定斑块相比，不稳定斑块中TF和HK-II的表达增加。CD68和HK-II免疫阳性细胞的数量与TF免疫阳性细胞的数量呈正相关。表达M1或M2样标志物的TF和HK-II阳性巨噬细胞参与了破裂斑块中血小板-纤维蛋白血栓的形成。炎症和缺氧条件的联合作用可叠加增强培养巨噬细胞中TF的表达和促凝血活性。用2-脱氧葡萄糖抑制糖酵解可降低增强的TF表达和促凝血活性。
动脉粥样硬化斑块中炎症和缺氧条件的联合作用可能会显著增强巨噬细胞的促凝血活性，并在斑块破裂后促进冠状动脉血栓形成。巨噬细胞TF表达可能与糖酵解有关。
