title: Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  Hematopoietic Hck/Fgr-deficient, LDLr(-/-) 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(high)-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, CARIM, Maastricht University Medical Center, Maastricht, the Netherlands.|Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: Indira
authors.initials: I
authors.lastname: Medina
authors.affiliation: CNRS; IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France.|Université de Toulouse, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Cougoule
authors.affiliation: Institute for Prevention of Cardiovascular Prevention (IPEK), LMU Munich, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Drechsler
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, CARIM, Maastricht University Medical Center, Maastricht, the Netherlands.|Department of Pharmacology, School of Pharmacy, University of Seville, Sevilla, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bermudez
authors.affiliation: Institute for Prevention of Cardiovascular Prevention (IPEK), LMU Munich, Germany.
authors.forename: Rory R
authors.initials: RR
authors.lastname: Koenen
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, CARIM, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Sluimer
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, CARIM, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Ine
authors.initials: I
authors.lastname: Wolfs
authors.affiliation: Institute for Prevention of Cardiovascular Prevention (IPEK), LMU Munich, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Döring
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, CARIM, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Veronica
authors.initials: V
authors.lastname: Herias
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, CARIM, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Marjon
authors.initials: M
authors.lastname: Gijbels
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: de Jager
authors.affiliation: Institute for Prevention of Cardiovascular Prevention (IPEK), LMU Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, CARIM, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Jack
authors.initials: J
authors.lastname: Cleutjens
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: Theo J C
authors.initials: TJC
authors.lastname: van Berkel
authors.affiliation: Department of Vascular Surgery, Orbis Hospital Sittard, The Netherlands.
authors.forename: Kees-Jan
authors.initials: KJ
authors.lastname: Sikkink
authors.affiliation: Department of Physiology; Semmelweis University, Budapest, Hungary.
authors.forename: Atilla
authors.initials: A
authors.lastname: Mócsai
authors.affiliation: CNRS; IPBS (Institut de Pharmacologie et de Biologie Structurale), Toulouse, France.|Université de Toulouse, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maridonneau-Parini
authors.affiliation: Institute for Prevention of Cardiovascular Prevention (IPEK), LMU Munich, Germany.|Department of Pathology, Academic Medical Center (AMC), Amsterdam, the Netherlands.|German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.affiliation: Experimental Vascular Pathology group, Department of Pathology, CARIM, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Erik A L
authors.initials: EAL
authors.lastname: Biessen
mesh_terms: D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D022081:Cell Surface Extensions / Q000648:ultrastructure; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D042783:Endothelial Cells; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D036904:Leukocyte Rolling; D017737:Macrophages, Peritoneal / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology*; D010587:Phagocytosis; D058226:Plaque, Atherosclerotic / Q000201:enzymology / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051572:Proto-Oncogene Proteins c-hck / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011828:Radiation Chimera; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D057705:Transendothelial and Transepithelial Migration; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases
keywords: atherosclerosis; cell migration assays; immunology; leukocytes; mobility; phosphotransferases; plaque, atherosclerotic