title: Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques.
abstract: BACKGROUND
  We previously showed that early calcification of atherosclerotic plaques associates with macrophage accumulation. Chronic renal disease and mineral imbalance accelerate calcification and the subsequent release of matrix vesicles (MVs), precursors of microcalcification.
  
  
  OBJECTIVE
  We tested the hypothesis that macrophage-derived MVs contribute directly to microcalcification.
  
  
  RESULTS
  Macrophages associated with regions of calcified vesicular structures in human carotid plaques (n=136 patients). In vitro, macrophages released MVs with high calcification and aggregation potential. MVs expressed exosomal markers (CD9 and TSG101) and contained S100A9 and annexin V. Silencing S100A9 in vitro and genetic deficiency in S100A9-/- mice reduced MV calcification, whereas stimulation with S100A9 increased calcification potential. Externalization of phosphatidylserine after Ca/P stimulation and interaction of S100A9 and annexin V indicated that a phosphatidylserine-annexin V-S100A9 membrane complex facilitates hydroxyapatite nucleation within the macrophage-derived MV membrane.
  
  
  CONCLUSIONS
  Our results support the novel concept that macrophages release calcifying MVs enriched in S100A9 and annexin V, which contribute to accelerated microcalcification in chronic renal disease.
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sophie E P
authors.initials: SE
authors.lastname: New
authors.forename: Claudia
authors.initials: C
authors.lastname: Goettsch
authors.forename: Masanori
authors.initials: M
authors.lastname: Aikawa
authors.forename: Julio F
authors.initials: JF
authors.lastname: Marchini
authors.forename: Manabu
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Katsumi
authors.initials: K
authors.lastname: Yabusaki
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000494:pharmacology; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D022162:Cytoplasmic Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D017886:Durapatite / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000648:ultrastructure; D017737:Macrophages, Peritoneal / Q000502:physiology; D008563:Membrane Lipids / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010718:Phosphatidylserines / Q000378:metabolism; D010758:Phosphorus / Q000494:pharmacology; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D017304:Annexin A5; D001057:Apolipoproteins E; D040502:Calgranulin B; D008563:Membrane Lipids; D008565:Membrane Proteins; D010718:Phosphatidylserines; D034741:RNA, Small Interfering; C576329:S100A9 protein, mouse; D010758:Phosphorus; D017886:Durapatite; D002118:Calcium
keywords: atherosclerosis; calcification; extracellular vesicles; inflammation; macrophages; renal insufficiency, chronic; rupture