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医学部 医学科 病理学講座構造機能病態学分野 |
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論文 【 表示 ／ 非表示 】
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中村恵理子
Plos One 18 ( 2 ) e0281730 2023年2月
担当区分：筆頭著者 記述言語：英語 掲載種別：学位論文（博士） 出版者・発行元：PLOS
Inflammatory activity and hypoxia in atherosclerotic plaques are associated with plaque instability and thrombotic complications. Recent studies show that vascular cell metabolism affects atherogenesis and thrombogenicity. This study aimed to identify the metabolites in macrophage-rich unstable plaques that modulate atherogenesis and serve as potential markers of plaque instability. Atherosclerotic plaques were induced by balloon injury in the iliofemoral arteries of rabbits fed on a conventional or 0.5% cholesterol diet. At 3 months post-balloon injury, the arteries and cardiac tissues were subjected to histological, quantitative real-time polymerase chain reaction, and metabolomic analyses. The identified metabolite-related proteins were immunohistochemically analyzed in stable and unstable plaques from human coronary arteries. The factors modulating the identified metabolites were examined in macrophages derived from human peripheral blood mononuclear cells. Metabolomic analysis revealed that choline and guanine levels in macrophage-rich arteries were upregulated compared with those in non-injured arteries and cardiac tissues. Vascular choline levels, but not guanine levels, were positively correlated with the areas immunopositive for macrophages and tumor necrosis factor (TNF)-α and matrix metalloproteinase (MMP) 9 mRNA levels in injured arteries. In human coronary arteries, choline transporter-like protein (CTL) 1 was mainly localized to macrophages within plaques. The area that was immunopositive for CTL1 in unstable plaques was significantly higher than that in stable plaques. Intracellular choline levels were upregulated upon stimulation with TNF-α but were downregulated under hypoxia in cultured macrophages. Administration of choline upregulated the expression of TNF-α and CTL1 mRNA in cultured macrophages. The transfection of CTL1 small interfering RNA decreased CTL1, TNF-α, and MMP9 mRNA levels in cultured macrophages. These results suggest that choline metabolism is altered in macrophage-rich atherosclerotic lesions and unstable plaques. Thus, CTL1 may be potential markers of plaque instability.
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Nakamura E., Sato Y., Iwakiri T., Yamashita A., Moriguchi-Goto S., Maekawa K., Gi T., Asada Y.
Journal of Atherosclerosis and Thrombosis 24 ( 9 ) 921 - 927 2017年9月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Atherosclerosis and Thrombosis
Aim: Patients with peripheral artery disease (PAD) have a high prevalence of cardiovascular morbidity and mortality; however, majority of patients with PAD are asymptomatic. This study aimed to histologically evaluate whether asymptomatic, lower extremity artery plaques are associated with systemic atherosclerosis and the onset of cardiovascular disease (CVD) events using autopsy cases. Methods: We histologically investigated the atherosclerotic plaques of the common iliac, common carotid, coronary, and renal arteries from 121 autopsy cases without symptoms of PAD (mean age: 67.6 years; 63% men; 83% non-CVD death). We evaluated the relationship between the degree of iliac artery atherosclerosis and that of other arteries, and also the presence of any CVD, myocardial infarction, stroke, and renal failure. Results: Advanced atherosclerotic plaques (American Heart Association ≥4) were present in 86 (72%) common iliac arteries in these cases. These arteries also showed high frequencies of calcification (66%), intraplaque hemorrhage (42%), and plaque disruption (24%). These advanced lesions were associated with age (≥ 60 years), sex (male), hypertension, diabetes, and smoking habit (all P＜0.05). Additionally, it was significantly associated with CVD (odds ratio, 95% confidence interval; 6.2, 2.2–22), myocardial infarction (6.4, 1.2– 19), stroke (8.7, 1.7 – 16), and renal failure/hemodialysis (5.8, 1.1 – 11). Cases with advanced iliac artery plaques had advanced coronary and carotid atherosclerosis. Conclusion: These results indicate that asymptomatic advanced plaques are frequently observed in common iliac arteries, and are associated with generalized atherosclerosis and CVD events.
DOI： 10.5551/jat.39669
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前川 和也, 中村 恵理子, 西東 洋一, 松浦 祐之介, 魏 峻洸, 大栗 伸行, 盛口 清香, 佐藤 勇一郎, 海北 幸一, 浅田 祐士郎, 山下 篤
PLoS ONE 20 ( 3 March ) e0316474 2025年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Public Library of Science (PLoS)
Background
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.
Aims
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.
Methods
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.
Results
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.
Conclusion
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. -
大栗 伸行, 魏 峻洸, 中村 恵理子, 前川 和也, 古小路 英二, 澤口 朗, 榮 建文, 東 美菜子, 浅田 祐士郎, 山下 篤
Research and Practice in Thrombosis and Haemostasis 9 ( 2 ) 102720 2025年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Elsevier BV
Background
Novel anticoagulants targeting coagulation factor (F)XI/activated FXI (FXIa) are currently under development. However, whether FXI is present in human deep vein thrombosis (DVT) and whether FXIa and activated FX (FXa) play different roles in venous thrombus formation and hemostasis remain unclear.
Objectives
To determine the presence of FXI in DVT and the effects of direct oral FXIa and FXa inhibitors on venous thrombus formation and hemostasis in rabbits and on in vitro thrombus formation.
Methods
We immunohistochemically assessed FXI localization in human-aspirated DVT (n = 15). Additionally, we compared thrombus formation induced by endothelial denudation and stenosis or stasis in the jugular vein and skin bleeding time and volume between rabbits treated with direct FXIa inhibitors (ONO-1600586) and FXa inhibitors (rivaroxaban). Ex vivo rabbit and human blood were perfused in a flow chamber under low-shear rates (70/s).
Results
FXI was localized in all DVT, predominantly in fibrin-rich areas. The FXI immunopositive area in the nonorganizing area was greater than that in the organizing area. Although FXIa and FXa inhibitors comparably inhibited venous thrombus formation, FXIa inhibitors did not affect bleeding time or volume in rabbits. FXIa or FXa inhibitors mildly or strongly inhibited fibrin formation at low-shear rates, respectively. Furthermore, the FXIa inhibitor suppressed human FXIa activity, thrombin generation, and fibrin formation during perfusion.
Conclusion
The pathologic findings of human DVT suggest FXI’s role in human DVT. FXIa inhibitors may inhibit less fibrin formation than FXa inhibitors and may explain the minor role of FXIa in hemostasis. -
Expression of fibroblast activation protein-α in human deep vein thrombosis 査読あり
魏 峻洸, 中村 恵理子, 古小路 英二, 後藤 洋規, 前川 和也, 阿萬 紫, 盛口 清香, 榮 建文, 東 美菜子, 山下 篤
Thrombosis Research 241 109075 2024年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Elsevier BV
Background
Fibroblast activation protein-α (FAP), a type-II transmembrane serine protease, is associated with wound healing, cancer-associated fibroblasts, and chronic fibrosing diseases. However, its expression in deep vein thrombosis (DVT) remains unclear. Therefore, this study investigated FAP expression and localization in DVT.
Methods
We performed pathological analyses of the aspirated thrombi of patients with DVT (n = 14), classifying thrombotic areas in terms of fresh, cellular lysis, and organizing reaction components. The organizing reaction included endothelialization and fibroblastic reaction. We immunohistochemically examined FAP-expressed areas and cells, and finally analyzed FAP expression in cultured dermal fibroblasts.
Results
All the aspirated thrombi showed a heterogeneous mixture of at least two of the three thrombotic areas. Specifically, 83 % of aspirated thrombi showed fresh and organizing reaction components. Immunohistochemical expression of FAP was restricted to the organizing area. Double immunofluorescence staining showed that FAP in the thrombi was mainly expressed in vimentin-positive or α-smooth muscle actin-positive fibroblasts. Some CD163-positive macrophages expressed FAP. FAP mRNA and protein levels were higher in fibroblasts with low-proliferative activity cultured under 0.1 % fetal bovine serum (FBS) than that under 10 % FBS. Fibroblasts cultured in 10 % FBS showed a significant decrease in FAP mRNA levels following supplementation with hemin, but not with thrombin.
Conclusions
The heterogeneous composition of venous thrombi suggests a multistep thrombus formation process in human DVT. Further, fibroblasts or myofibroblasts may express FAP during the organizing process. FAP expression may be higher in fibroblasts with low proliferative activity.
科研費（文科省・学振・厚労省）獲得実績 【 表示 ／ 非表示 】
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大動脈瘤化を促進する壁内細胞の代謝変化とその血液指標の同定
研究課題/領域番号：23K19470 2023年04月 - 2025年03月
独立行政法人日本学術振興会 科学研究費基金 研究活動スタート支援
中村 恵理子
担当区分：研究代表者
概要：
大動脈瘤発生の多くが動脈硬化を基盤としており、無症候性に徐々に進行し、突然破裂して発症する。破裂時の致死率が40%と高値であることから、有効な予防薬や、破裂リスクの評価方法の確立が望まれている。申請者は、大動脈瘤症例の血管標本の代謝解析でトリプトファンのキヌレニン代謝経路が亢進していることなどを明らかにし、動脈硬化巣に存在する細胞の代謝と病態への関与に注目して研究している。本研究では、大動脈瘤症例の血液サンプル、大動脈標本、培養細胞などを用いて、大動脈瘤の大きさと関連する血液の代謝産物を同定し、その大動脈瘤化における役割を明らかにすることを目的とする。
研究成果：
①動脈硬化性大動脈瘤で血管手術を施行された55症例を用いて、CT検査で大動脈の最大瘤径や瘤容積を計測した。血清のメタボローム解析で極性代謝産物を測定し、相関解析で、最大瘤径や瘤容積と相関する血液代謝産物を同定した。解糖系代謝産物の一つなどが最大瘤径と相関することを確認している。②次に、摘出された大動脈を早期病変、進行動脈硬化病変、大動脈瘤に分類し同定した代謝酵素の発現を3群比較した。③さらに、免疫組織化学で同定した代謝酵素の発現細胞を検討した。これまでにマクロファージや平滑筋細胞の一部が同定した代謝酵素を発現することを確認した。画像解析で免疫組織化学陽性面積率を計測したところ、同定した代謝酵素は進行性動脈硬化病変や大動脈瘤で増加していた。
④ヒト末梢血由来単球を培地内で分化させ、炎症性サイトカイン刺激を加えた際の同定した代謝酵素や炎症関連・動脈硬化不安定化関連遺伝子の発現変化を、PCRを用いて調べる予備検討を行った。 -
動脈硬化巣の破綻に関連する石灰化結節の病理と石灰化機序の解明
研究課題/領域番号：25K18753 2025年04月 - 2028年03月
独立行政法人日本学術振興会 科学研究費基金 若手研究
担当区分：研究代表者