Watanabe Yuki, Koyama Shohei, Yamashita Atsushi, Matsuura Yunosuke, Nishihira Kensaku, Kitamura Kazuo, Asada Yujiro
Department of Pathology Faculty of Medicine University of Miyazaki Miyazaki Japan.
Department of Internal Medicine Faculty of Medicine University of Miyazaki Miyazaki Japan.
Res Pract Thromb Haemost. 2018 Jul 13;2(4):726-735. doi: 10.1002/rth2.12128. eCollection 2018 Oct.
Recent clinical studies have found that changes in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism are associated with cardiovascular events. However, the roles of the Kyn pathway on vascular wall thrombogenicity remain unknown. Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme of the Kyn pathway.
The present study aimed to localize IDO1 in human coronary atherosclerotic plaques from patients with angina pectoris and define its role in plaque thrombogenicity.
Immunohistochemical methods were applied to localize IDO1 in coronary atherosclerotic plaques from patients with stable (SAP) and unstable (UAP) angina pectoris. The role of IDO1 in tissue factor (TF) expression was investigated in THP-1 macrophages activated by interferon (IFN)γ and tissue necrosis factor (TNF)α.
We localized IDO1 mainly in CD68-positive macrophages within atherosclerotic plaques, and in close association with TF. Areas that were immunopositive for IDO1, TF, and CD3-positive T lymphocytes were significantly larger in plaques from patients with UAP than SAP. Macrophages activated by IFNγ and TNFα upregulated IDO1 expression, increased the Kyn/Trp ratio and enhanced TF expression and activity, but not TF pathway inhibitor expression. The IDO1 inhibitor epacadostat significantly reduced the Kyn/Trp ratio, TF expression and activity, as well as NF-κB (p65) binding activity in activated macrophages. Inhibition of the aryl hydrocarbon receptor that binds to Kyn, also reduced Kyn-induced TF expression in activated macrophages.
Indoleamine 2,3-dioxygenase 1 expressed in coronary atherosclerotic plaques might contribute to thrombus formation through TF upregulation in activated macrophages.
近期临床研究发现，色氨酸（Trp）代谢的犬尿氨酸（Kyn）途径变化与心血管事件相关。然而，Kyn途径在血管壁血栓形成性方面的作用尚不清楚。吲哚胺2,3-双加氧酶1（IDO1）是Kyn途径的限速酶。
本研究旨在确定IDO1在心绞痛患者的人冠状动脉粥样硬化斑块中的定位，并明确其在斑块血栓形成性中的作用。
应用免疫组织化学方法在稳定型心绞痛（SAP）和不稳定型心绞痛（UAP）患者的冠状动脉粥样硬化斑块中定位IDO1。在经干扰素（IFN）γ和肿瘤坏死因子（TNF）α激活的THP-1巨噬细胞中研究IDO1在组织因子（TF）表达中的作用。
我们发现IDO1主要定位于动脉粥样硬化斑块内的CD68阳性巨噬细胞中，且与TF密切相关。UAP患者斑块中IDO1、TF和CD3阳性T淋巴细胞免疫阳性区域显著大于SAP患者。经IFNγ和TNFα激活的巨噬细胞上调IDO1表达，增加Kyn/Trp比值，增强TF表达和活性，但不增加TF途径抑制剂表达。IDO1抑制剂依帕司他显著降低激活巨噬细胞中的Kyn/Trp比值、TF表达和活性以及NF-κB（p65）结合活性。抑制与Kyn结合的芳烃受体也可降低Kyn诱导的激活巨噬细胞中TF表达。
冠状动脉粥样硬化斑块中表达的吲哚胺2,3-双加氧酶1可能通过激活巨噬细胞中TF上调促进血栓形成。
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