title: Expression of human tissue factor pathway inhibitor on vascular smooth muscle cells inhibits secretion of macrophage migration inhibitory factor and attenuates atherosclerosis in ApoE-/- mice.
abstract: BACKGROUND
  Tissue factor (TF) and coagulation proteases are involved in promoting atherosclerosis, but the molecular and cellular bases for their involvement are unknown.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: 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.). anthony.dorling@kcl.ac.uk daxin.chen@kcl.ac.uk.
authors: Daxin
authors: D
authors: Chen
authors: 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.).
authors: Min
authors: M
authors: Xia
authors: 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.).
authors: Claudia
authors: C
authors: Hayford
authors: 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.).
authors: El-Li
authors: el-L
authors: Tham
authors: 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.).
authors: Vikki
authors: V
authors: Semik
authors: 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.).
authors: Stuart
authors: S
authors: Hurst
authors: 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.).
authors: Ying
authors: Y
authors: Chen
authors: 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.).
authors: Henry H
authors: HH
authors: Tam
authors: 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.).
authors: Jun
authors: J
authors: Pan
authors: 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.).
authors: Yucheng
authors: Y
authors: Wang
authors: 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.).
authors: Xiaojin
authors: X
authors: Tan
authors: 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.).
authors: Hui-Yao
authors: HY
authors: Lan
authors: 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.).
authors: Huahao
authors: H
authors: Shen
authors: 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.).
authors: Vijay V
authors: VV
authors: Kakkar
authors: 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.).
authors: Qingbo
authors: Q
authors: Xu
authors: 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.).
authors: John H
authors: JH
authors: McVey
authors: 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.). anthony.dorling@kcl.ac.uk daxin.chen@kcl.ac.uk.
authors: Anthony
authors: A
authors: Dorling
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D007962:Leukocytes / Q000473:pathology; D050356:Lipid Metabolism / Q000502:physiology; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001057:Apolipoproteins E; D008074:Lipoproteins; D008263:Macrophage Migration-Inhibitory Factors; C051928:lipoprotein-associated coagulation inhibitor
keywords: anticoagulants; atherosclerosis; inflammation; muscle, smooth