Daxin Chen1, Min Xia2, Claudia Hayford2, El-Li Tham2, Vikki Semik2, Stuart Hurst2, Ying Chen2, Henry H Tam2, Jun Pan2, Yucheng Wang2, Xiaojin Tan2, Hui-Yao Lan2, Huahao Shen2, Vijay V Kakkar2, Qingbo Xu2, John H McVey2, Anthony Dorling1. 1. 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. 2. 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.).
Abstract
BACKGROUND: Tissue factor (TF) and coagulation proteases are involved in promoting atherosclerosis, but the molecular and cellular bases for their involvement are unknown. METHODS AND 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.
BACKGROUND: Tissue factor (TF) and coagulation proteases are involved in promoting atherosclerosis, but the molecular and cellular bases for their involvement are unknown. METHODS AND 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: Corinna Schmitz; Heidi Noels; Omar El Bounkari; Eva Straussfeld; Remco T A Megens; Marieke Sternkopf; Setareh Alampour-Rajabi; Christine Krammer; Pathricia V Tilstam; Norbert Gerdes; Christina Bürger; Aphrodite Kapurniotu; Richard Bucala; Joachim Jankowski; Christian Weber; Jürgen Bernhagen Journal: FASEB J Date: 2018-03-15 Impact factor: 5.191
Authors: Qi Peng; Kulachelvy Ratnasothy; Dominic A Boardman; Jacinta Jacob; Sim Lai Tung; Daniel McCluskey; Lesley A Smyth; Robert I Lechler; Anthony Dorling; Giovanna Lombardi Journal: Front Immunol Date: 2019-06-18 Impact factor: 7.561
Authors: Daxin Chen; Ke Li; El-Li Tham; Lin-Lin Wei; Ning Ma; Philippa C Dodd; Yi Luo; Daniel Kirchhofer; John H McVey; Anthony Dorling Journal: Front Immunol Date: 2018-07-02 Impact factor: 7.561