title: Loss of Id3 increases VCAM-1 expression, macrophage accumulation, and atherogenesis in Ldlr-/- mice.
abstract: OBJECTIVE
  Inhibitor of differention-3 (Id3) promotes B cells homing to the aorta and atheroprotection in Apoe(-/-) mice. We sought to determine the impact of loss of Id3 in the Ldlr((-/-)) mouse model of diet-induced atherosclerosis and identify novel Id3 targets in the vessel wall.
  
  
  RESULTS
  Ex vivo optical imaging confirmed that Id3((-/-)) Ldlr((-/-)) mice have significantly fewer aortic B cells than Id3((+/+)) Ldlr(-/-) mice. After 8 and 16 weeks of Western diet, Id3((-/-)) Ldlr((-/-)) mice developed significantly more atherosclerosis than Id3((+/+)) Ldlr((-/-)) mice, with Id3(+/-) Ldlr(-/-) mice demonstrating an intermediate phenotype. There were no differences in serum lipid levels between genotypes. Immunostaining demonstrated that aortas from Id3((-/-)) Ldlr((-/-)) mice had greater intimal macrophage density and C-C chemokine ligand 20 and vascular cell adhesion molecule 1 (VCAM-1) expression compared with Id3((+/+)) Ldlr(-/-) mice. Real-time polymerase chain reaction demonstrated increased VCAM-1 mRNA levels in the aortas of Id3(-/-) Ldlr(-/-) mice. Primary vascular smooth muscle cells from Id3((-/-)) mice expressed greater amounts of VCAM-1 protein compared with control. Gain and loss of function studies in primary vascular smooth muscle cells identified a role for Id3 in repressing VCAM-1 promoter activation. Chromatin immunoprecipitation demonstrated interaction of E12 with the VCAM-1 promoter, which is inhibited by Id3.
  
  
  CONCLUSIONS
  Id3 is an atheroprotective transcription regulator with targets in both B cells and vessel wall cells leading to reduced macrophage accumulation and reduced atherosclerosis formation.
authors.affiliation: Cardiovascular Research Center, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lipinski
authors.forename: Kirsti A
authors.initials: KA
authors.lastname: Campbell
authors.forename: Son Q
authors.initials: SQ
authors.lastname: Duong
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Welch
authors.forename: James C
authors.initials: JC
authors.lastname: Garmey
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Doran
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Skaflen
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Oldham
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Kelly
authors.forename: Coleen A
authors.initials: CA
authors.lastname: McNamara
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D054418:Chemokine CCL20 / Q000378:metabolism; D004195:Disease Models, Animal; D051796:Inhibitor of Differentiation Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D015995:Prevalence; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; D051796:Inhibitor of Differentiation Proteins; D011973:Receptors, LDL; D019010:Vascular Cell Adhesion Molecule-1; C067679:Idb3 protein, mouse