title: Promoting macrophage survival delays progression of pre-existing atherosclerotic lesions through macrophage-derived apoE.
abstract: OBJECTIVE
  Macrophage apoptosis is a prominent feature of atherosclerosis, yet whether cell death-protected macrophages would favour the resolution of already established atherosclerotic lesions, and thus hold therapeutic potential, remains unknown.
  
  
  RESULTS
  We irradiated then transplanted into Apoe(-/-) or LDLr(-/-) recipient mice harbouring established atherosclerotic lesions, bone marrow cells from mice displaying enhanced macrophage survival through overexpression of the antiapoptotic gene hBcl-2 (Mø-hBcl2 Apoe(-/-) or Mø-hBcl2 Apoe(+/+) LDLr(-/-)). Both recipient mice exhibited decreased lesional apoptotic cell content and reduced necrotic areas when repopulated with Mø-hBcl2 mouse-derived bone marrow cells. In contrast, only LDLr(-/-) recipients showed a reduction in plasma cholesterol levels and in atherosclerotic lesions. The absence of significant reduction of plasma cholesterol levels in the context of apoE deficiency highlighted macrophage-derived apoE as key in both the regulation of plasma and tissue cholesterol levels and the progression of pre-existing lesion. Accordingly, hBcl2 expression in macrophages was associated with larger pools of Kupffer cells and Ly-6C(low) monocytes, both high producers of apoE. Additionally, increased Kupffer cells population was associated with improved clearance of apoptotic cells and modified lipoproteins.
  
  
  CONCLUSIONS
  Collectively, these data show that promoting macrophage survival provides a supplemental source of apoE, which hinders pre-existing plaque progression.
authors.affiliation: INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Bouchareychas
authors.affiliation: INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France.
authors.forename: John
authors.initials: J
authors.lastname: Pirault
authors.affiliation: INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Saint-Charles
authors.affiliation: INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Deswaerte
authors.affiliation: INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Institute of Cardiometabolism and Nutrition, ICAN, AP-HP, Pitié-Salpêtrière Hospital, Paris F-75013, France.
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Le Roy
authors.affiliation: Atherosclerosis Group, ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia.
authors.forename: Wendy
authors.initials: W
authors.lastname: Jessup
authors.affiliation: INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Institute of Cardiometabolism and Nutrition, ICAN, AP-HP, Pitié-Salpêtrière Hospital, Paris F-75013, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Giral
authors.affiliation: INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France Institute of Cardiometabolism and Nutrition, ICAN, AP-HP, Pitié-Salpêtrière Hospital, Paris F-75013, France.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Le Goff
authors.affiliation: INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France Institute of Cardiometabolism and Nutrition, ICAN, AP-HP, Pitié-Salpêtrière Hospital, Paris F-75013, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Huby
authors.affiliation: INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France Institute of Cardiometabolism and Nutrition, ICAN, AP-HP, Pitié-Salpêtrière Hospital, Paris F-75013, France philippe.lesnik@upmc.fr emmanuel-laurent.gautier@inserm.fr.
authors.forename: Emmanuel L
authors.initials: EL
authors.lastname: Gautier
authors.affiliation: INSERM, UMR_S U1166, Integrative Biology of Atherosclerosis Team, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de L'hôpital, Paris F-75013, France Sorbonne Universités, UPMC Université Paris 06, UMR_S 1166, ICAN, Integrative Biology of Atherosclerosis Team, Paris F-75005, France Institute of Cardiometabolism and Nutrition, ICAN, AP-HP, Pitié-Salpêtrière Hospital, Paris F-75013, France philippe.lesnik@upmc.fr emmanuel-laurent.gautier@inserm.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lesnik
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000502:physiology; D001057:Apolipoproteins E / Q000502:physiology*; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology*; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism; D018450:Disease Progression; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011973:Receptors, LDL / Q000502:physiology
chemical_list: D000950:Antigens, Ly; D001057:Apolipoproteins E; C494192:Ly-6C antigen, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D011973:Receptors, LDL; D002784:Cholesterol
keywords: Apolipoprotein E; Apoptosis; Atherosclerosis; Cholesterol; Macrophage