title: ApoE suppresses atherosclerosis by reducing lipid accumulation in circulating monocytes and the expression of inflammatory molecules on monocytes and vascular endothelium.
abstract: OBJECTIVE
  We investigated atheroprotective properties of apolipoprotein (apo) E beyond its ability to lower plasma cholesterol. We hypothesized that apoE reduces atherosclerosis by decreasing lipid accumulation in circulating monocytes and the inflammatory state of monocytes and the vascular endothelium.
  
  
  RESULTS
  We developed mice with spontaneous hyperlipidemia with and without plasma apoE. Hypomorphic apoE mice deficient in low-density lipoprotein receptor (Apoe(h/h)Ldlr(-/-)) were compared to Apoe(-/-)Ldlr(-/-) mice. Despite 4-fold more plasma apoE than WT mice, Apoe(h/h)Ldlr(-/-) mice displayed similar plasma cholesterol as Apoe(-/-) Ldlr(-/-) mice but developed 4-fold less atherosclerotic lesions by 5 months of age. The aortic arch of Apoe(h/h)Ldlr(-/-) mice showed decreased endothelial expression of ICAM-1, PECAM-1, and JAM-A. In addition, Apoe(h/h)Ldlr(-/-) mice had less circulating leukocytes and proinflammatory Ly6C(high) monocytes. These monocytes had decreased neutral lipid content and reduced surface expression of ICAM-1, VLA-4, and L-Selectin. Apoe(h/h)Ldlr(-/-) mice displayed increased levels of apoA1-rich HDL that were potent in promoting cellular cholesterol efflux.
  
  
  CONCLUSIONS
  Our findings suggest that apoE reduces atherosclerosis in the setting of hyperlipidemia by increasing plasma apoA1-HDL that likely contribute to reduce intracellular lipid accumulation and thereby the activation of circulating leukocytes and the vascular endothelium.
authors: Department of Surgery, University of California San Francisco and VA Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA.
authors: Nathalie
authors: N
authors: Gaudreault
authors: Nikit
authors: N
authors: Kumar
authors: Jessica M
authors: JM
authors: Posada
authors: Kyle B
authors: KB
authors: Stephens
authors: Nabora Soledad
authors: NS
authors: Reyes de Mochel
authors: Delphine
authors: D
authors: Eberlé
authors: Victor R
authors: VR
authors: Olivas
authors: Roy Y
authors: RY
authors: Kim
authors: Matthew J
authors: MJ
authors: Harms
authors: Sean
authors: S
authors: Johnson
authors: Louis M
authors: LM
authors: Messina
authors: Joseph H
authors: JH
authors: Rapp
authors: Robert L
authors: RL
authors: Raffai
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism* / Q000517:prevention & control*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D039041:Integrin alpha4beta1 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; C498686:F11r protein, mouse; D018836:Inflammation Mediators; D039041:Integrin alpha4beta1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; D002784:Cholesterol