title: Cholate-containing high-fat diet induces the formation of multinucleated giant cells in atherosclerotic plaques of apolipoprotein E-/- mice.
abstract: OBJECTIVE
  To determine the role of multinucleated giant cells (MGCs) in cardiovascular diseases.
  
  
  RESULTS
  MGCs are a hallmark of giant cell arteritis. They are also described in atherosclerotic plaques from aortic aneurysms and carotid and coronary arteries. Herein, we demonstrate that the cholate-containing Paigen diet yields many MGCs in atherosclerotic plaques of apolipoprotein E-/- mice. These mice revealed a 4-fold increase in MGC numbers when compared with mice on a Western or Paigen diet without cholate. Most of the MGCs stained intensively for cathepsin K and were located at fibrous caps and close to damaged elastic laminae, with associated medial smooth muscle cell depletion. During in vitro experiments, MGCs demonstrated a 6-fold increase in elastolytic activity when compared with macrophages and facilitated transmigration of smooth muscle cells through a collagen-elastin matrix. An elastin-derived hexapeptide (Val-Gly-Val-Ala-Pro-Gly [VGVAPG]) significantly increased the rate of macrophage fusion, providing a possible mechanism of in vivo MGC formation. Comparable to the mouse model, human specimens from carotid arteries and aortic aneurysms contained cathepsin K-positive MGCs.
  
  
  CONCLUSIONS
  Apolipoprotein E-/- mice fed a Paigen diet provide a model to analyze the tissue-destructive role of MGCs in vascular diseases.
authors.affiliation: Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Andriy O
authors.initials: AO
authors.lastname: Samokhin
authors.forename: Susan
authors.initials: S
authors.lastname: Wilson
authors.forename: Boram
authors.initials: B
authors.lastname: Nho
authors.forename: Maria Luisa Garcia
authors.initials: ML
authors.lastname: Lizame
authors.forename: Osvaldo E Eliseo
authors.initials: OE
authors.lastname: Musenden
authors.forename: Dieter
authors.initials: D
authors.lastname: Brömme
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001014:Aortic Aneurysm / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology; D056657:Cathepsin K / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002459:Cell Fusion; D002465:Cell Movement; D002478:Cells, Cultured; D020355:Cholates; D003094:Collagen / Q000378:metabolism; D004041:Dietary Fats; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D004731:Endotoxins / Q000097:blood; D015743:Giant Cells, Foreign-Body / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D015847:Interleukin-4 / Q000097:blood; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D001057:Apolipoproteins E; D020355:Cholates; D004041:Dietary Fats; D004731:Endotoxins; D009842:Oligopeptides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C036763:monocyte-macrophage differentiation antigen; D015847:Interleukin-4; D003094:Collagen; D004549:Elastin; C042635:valyl-glycyl-valyl-alanyl-prolyl-glycine; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse