From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S., K. Satoh, N.Y., N.K., J.O., R.K., K.N., E.A.-M., M.A.H.S., S.S., M.N., K. Suzuki, S.M., H.S.); and Department of Hematology, Stanford School of Medicine, CA (J.M.).
Circ Res. 2017 Apr 14;120(8):1246-1262. doi: 10.1161/CIRCRESAHA.117.310640. Epub 2017 Mar 13.
Pulmonary hypertension is a fatal disease; however, its pathogenesis still remains to be elucidated. Thrombin-activatable fibrinolysis inhibitor (TAFI) is synthesized by the liver and inhibits fibrinolysis. Plasma TAFI levels are significantly increased in chronic thromboembolic pulmonary hypertension (CTEPH) patients.
To determine the role of activated TAFI (TAFIa) in the development of CTEPH.
Immunostaining showed that TAFI and its binding partner thrombomodulin (TM) were highly expressed in the pulmonary arteries (PAs) and thrombus in patients with CTEPH. Moreover, plasma levels of TAFIa were increased 10-fold in CTEPH patients compared with controls. In mice, chronic hypoxia caused a 25-fold increase in plasma levels of TAFIa with increased plasma levels of thrombin and TM, which led to thrombus formation in PA, vascular remodeling, and pulmonary hypertension. Consistently, plasma clot lysis time was positively correlated with plasma TAFIa levels in mice. Additionally, overexpression of TAFIa caused organized thrombus with multiple obstruction of PA flow and reduced survival rate under hypoxia in mice. Bone marrow transplantation showed that circulating plasma TAFI from the liver, not in the bone marrow, was activated locally in PA endothelial cells through interactions with thrombin and TM. Mechanistic experiments demonstrated that TAFIa increased PA endothelial permeability, smooth muscle cell proliferation, and monocyte/macrophage activation. Importantly, TAFIa inhibitor and peroxisome proliferator-activated receptor-α agonists significantly reduced TAFIa and ameliorated animal models of pulmonary hypertension in mice and rats.
These results indicate that TAFIa could be a novel biomarker and realistic therapeutic target of CTEPH.
肺动脉高压是一种致命的疾病，但发病机制仍未阐明。血栓调节蛋白激活的纤溶抑制物（TAFI）由肝脏合成，可抑制纤维蛋白溶解。慢性血栓栓塞性肺动脉高压（CTEPH）患者的血浆 TAFI 水平显著升高。
确定活化的 TAFI（TAFIa）在 CTEPH 发展中的作用。
免疫染色显示，TAFI 及其结合伴侣血栓调节蛋白（TM）在 CTEPH 患者的肺动脉（PA）和血栓中高度表达。此外，CTEPH 患者的血浆 TAFIa 水平比对照组增加了 10 倍。在小鼠中，慢性缺氧导致血浆 TAFIa 水平增加 25 倍，同时伴有血浆中凝血酶和 TM 水平升高，导致 PA 血栓形成、血管重构和肺动脉高压。一致地，小鼠的血浆血栓溶解时间与血浆 TAFIa 水平呈正相关。此外，TAFIa 的过表达导致血栓形成伴有 PA 血流多处阻塞，并降低了缺氧条件下小鼠的存活率。骨髓移植表明，来自肝脏的循环血浆 TAFI 通过与凝血酶和 TM 的相互作用在 PA 内皮细胞中局部被激活，而不是在骨髓中。机制实验表明，TAFIa 增加了 PA 内皮通透性、平滑肌细胞增殖和单核细胞/巨噬细胞激活。重要的是，TAFIa 抑制剂和过氧化物酶体增殖物激活受体-α 激动剂可显著降低 TAFIa，并改善 CTEPH 小鼠和大鼠的肺动脉高压动物模型。
这些结果表明，TAFIa 可能是 CTEPH 的一种新型生物标志物和有治疗意义的靶点。
