Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility
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- Indira Medina
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Céline Cougoule
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Maik Drechsler
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Beatriz Bermudez
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Rory R. Koenen
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Judith Sluimer
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Ine Wolfs
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Yvonne Döring
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Veronica Herias
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Marjon Gijbels
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Ilze Bot
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Saskia C. A. de Jager
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Christian Weber
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Jack Cleutjens
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Theo J.C. van Berkel
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Kees-Jan Sikkink
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Atilla Mócsai
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Isabelle Maridonneau-Parini
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Oliver Soehnlein
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
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- Erik A.L. Biessen
- From Experimental Vascular Pathology Group, Department of Pathology, CARIM, Maastricht University Medical Center, The Netherlands (I.M., J.S., I.W., V.H., M.G., J.C., E.A.L.B.); Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands (I.M., I.B., S.C.A.d.J., T.J.C.v.B.); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France (C.C., I.M.-P.); Université de Toulouse, France (C.C., I.M.-P.); Institute for Prevention of...
抄録
<jats:sec> <jats:title>Background—</jats:title> <jats:p>Leukocyte migration is critical for the infiltration of monocytes and accumulation of monocyte-derived macrophages in inflammation. Considering that Hck and Fgr are instrumental in this process, their impact on atherosclerosis and on lesion inflammation and stability was evaluated.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> Hematopoietic Hck/Fgr-deficient, LDLr <jats:sup>−/−</jats:sup> chimeras, obtained by bone marrow transplantation, had smaller but, paradoxically, less stable lesions with reduced macrophage content, overt cap thinning, and necrotic core expansion as the most prominent features. Despite a Ly6C <jats:sup>high</jats:sup> -skewed proinflammatory monocyte phenotype, Hck/Fgr deficiency led to disrupted adhesion of myeloid cells to and transmigration across endothelial monolayers in vitro and atherosclerotic plaques in vivo, as assessed by intravital microscopy, flow cytometry, and histological examination of atherosclerotic arteries. Moreover, Hck/Fgr-deficient macrophages showed blunted podosome formation and mesenchymal migration capacity. In consequence, transmigrated double-knockout macrophages were seen to accumulate in the fibrous cap, potentially promoting its focal erosion, as observed for double-knockout chimeras. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>The hematopoietic deficiency of Hck and Fgr led to attenuated atherosclerotic plaque formation by abrogating endothelial adhesion and transmigration; paradoxically, it also promoted plaque instability by causing monocyte subset imbalance and subendothelial accumulation, raising a note of caution regarding src kinase–targeted intervention in plaque inflammation.</jats:p> </jats:sec>
収録刊行物
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- Circulation
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Circulation 132 (6), 490-501, 2015-08-11
Ovid Technologies (Wolters Kluwer Health)