From MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK (D.C., C.H., E.-L.T., V.S., S.H., J.H.M., A.D.); Thrombosis Research Institute, London, UK (M.X., V.V.K.); Department of Imaging, Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, UK (Y.C., H.H.T.); Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China (J.P., Y.W., H.L.); Department of Cardiovascular Medicine, First Affiliated Hospital of University of South China, Hengyang, China (X.T.); Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou and State Key Laboratory of Respiratory Disease, Guangzhou, China (H.S.); Cardiovascular Division, King's College London British Heart Foundation (James Black) Centre, London, UK (Q.X.); and Molecular Medicine Group, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (J.H.M.).
Circulation. 2015 Apr 14;131(15):1350-60. doi: 10.1161/CIRCULATIONAHA.114.013423. Epub 2015 Feb 12.
Tissue factor (TF) and coagulation proteases are involved in promoting atherosclerosis, but the molecular and cellular bases for their involvement are unknown.
We generated a new strain (ApX4) of apolipoprotein E-deficient mice expressing a membrane-tethered human tissue factor pathway inhibitor fusion protein on smooth muscle actin-positive cells, including vascular smooth muscle cells (SMCs). ApX4 mice developed little atherosclerosis on either a normal chow or high-fat diet. Lipid levels were similar to those in parental ApoE(-/-) mice, and there was no detectable difference in systemic (circulating) tissue factor pathway inhibitor levels or activity. The small lipid-rich lesions that developed had markedly reduced leukocyte infiltrates, and in contrast to ApoE(-/-) mice, SMCs did not express macrophage migratory inhibitory factor (MIF), including at sites distant from atheromatous lesions. Low levels of circulating MIF in ApX4 mice normalized to levels seen in ApoE(-/-) mice after injection of an inhibitory anti-human tissue factor pathway inhibitor antibody, which also led to MIF expression by tissue factor-positive medial SMCs. MIF production by SMCs in ApoE(-/-) mice in vitro and in vivo was shown to be dependent on tissue factor and protease-activated receptor signaling, which were inhibited in ApX4 mice.
Our data indicate that tissue factor plays a hitherto unreported role in the generation of MIF by SMCs in atherosclerosis-prone ApoE(-/-) mice, inhibition of which significantly prevents the development of atherosclerosis, through inhibition of leukocyte recruitment. These data significantly enhance our understanding of the pathophysiology of this important pathology and suggest new potential translational strategies to prevent atheroma formation.
组织因子（TF）和凝血蛋白酶参与促进动脉粥样硬化，但它们参与的分子和细胞基础尚不清楚。
我们生成了一种新的载脂蛋白 E 缺陷型小鼠株（ApX4），该小鼠在平滑肌肌动蛋白阳性细胞（包括血管平滑肌细胞[SMCs]）上表达一种膜结合的人组织因子途径抑制剂融合蛋白。ApX4 小鼠在正常饲料或高脂肪饮食中几乎没有发生动脉粥样硬化。脂质水平与亲本 ApoE（-/-）小鼠相似，系统（循环）组织因子途径抑制剂水平或活性没有差异。形成的小脂质丰富的病变有明显减少的白细胞浸润，与 ApoE（-/-）小鼠不同，SMCs 不表达巨噬细胞迁移抑制因子（MIF），包括远离粥样硬化病变的部位。ApX4 小鼠中循环 MIF 水平低，用抑制性抗人组织因子途径抑制剂抗体注射后，其水平可恢复到 ApoE（-/-）小鼠水平，这也导致组织因子阳性中膜 SMC 表达 MIF。在体外和体内，ApoE（-/-）小鼠中 SMC 产生的 MIF 依赖于组织因子和蛋白酶激活受体信号，在 ApX4 小鼠中这些信号被抑制。
我们的数据表明，组织因子在易发生动脉粥样硬化的 ApoE（-/-）小鼠中 SMC 产生 MIF 方面发挥了迄今未报道的作用，通过抑制白细胞募集，抑制组织因子可显著防止动脉粥样硬化的发生。这些数据显著增强了我们对这一重要病理学的病理生理学的理解，并为预防动脉粥样斑块形成提供了新的潜在转化策略。
