title: Bcl-x inactivation in macrophages accelerates progression of advanced atherosclerotic lesions in Apoe(-/-) mice.
abstract: OBJECTIVE
  Bcl-x is the most abundantly expressed member of the Bcl-2 gene family in macrophages, but its role in macrophage apoptosis during atherogenesis is unknown.
  
  
  RESULTS
  We previously reported dual pro- and antiatherogenic effects of macrophage survival in early versus advanced atherosclerotic lesions, respectively, potentially reflecting growing impairment of efferocytosis during plaque progression. Here, we specifically inactivated Bcl-x in macrophages and evaluated its impact on atherosclerotic lesion formation in Apoe(-/-) mice at various stages of the disease. Bcl-x deficiency in macrophages increased their susceptibility to apoptosis, resulting in the depletion of tissue macrophages in vivo, including its major pool, Küppfer cells in the liver. We also observed increased cholesterol levels that were, however, not associated with any acceleration of early atherosclerotic plaque progression. This observation suggests that the atheroprotective effect of macrophage apoptosis at that stage of disease was counterbalanced by enhanced cholesterol levels. Bcl-x KO(mac)/Apoe(-/-) mice exhibited significantly larger advanced lesions than control mice. These lesions showed vulnerable traits. Such enhanced lesion size may occur as a result not only of apoptotic cell accumulation but also of elevated cholesterol levels.
  
  
  CONCLUSIONS
  Modulation of macrophage resistance to apoptosis through targeted deletion of Bcl-x has a major impact on the entire macrophage cell population in the body, including Küpffer cells. Macrophage survival may, therefore, not only influence atherosclerotic plaque development and vulnerability but also cholesterol metabolism.
authors.affiliation: INSERM UMR-S 939, Hôpital de la Pitié, F-75013, Paris, France.
authors.forename: Andrew I U
authors.initials: AI
authors.lastname: Shearn
authors.forename: Virginie
authors.initials: V
authors.lastname: Deswaerte
authors.forename: Emmanuel L
authors.initials: EL
authors.lastname: Gautier
authors.forename: Flora
authors.initials: F
authors.lastname: Saint-Charles
authors.forename: John
authors.initials: J
authors.lastname: Pirault
authors.forename: Laura
authors.initials: L
authors.lastname: Bouchareychas
authors.forename: Edmund B
authors.initials: EB
authors.lastname: Rucker
authors.forename: Sophie
authors.initials: S
authors.lastname: Beliard
authors.forename: John
authors.initials: J
authors.lastname: Chapman
authors.forename: Wendy
authors.initials: W
authors.lastname: Jessup
authors.forename: Thierry
authors.initials: T
authors.lastname: Huby
authors.forename: Philippe
authors.initials: P
authors.lastname: Lesnik
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; D051020:bcl-X Protein; D004247:DNA