title: Loss of one copy of Zfp148 reduces lesional macrophage proliferation and atherosclerosis in mice by activating p53.
abstract: BACKGROUND
  Cell proliferation and cell cycle control mechanisms are thought to play central roles in the pathogenesis of atherosclerosis. The transcription factor Zinc finger protein 148 (Zfp148) was shown recently to maintain cell proliferation under oxidative conditions by suppressing p53, a checkpoint protein that arrests proliferation in response to various stressors. It is established that inactivation of p53 accelerates atherosclerosis, but whether increased p53 activation confers protection against the disease remains to be determined.
  
  
  OBJECTIVE
  We aimed to test the hypothesis that Zfp148 deficiency reduces atherosclerosis by unleashing p53 activity.
  
  
  RESULTS
  Mice harboring a gene-trap mutation in the Zfp148 locus (Zfp148(gt/+)) were bred onto the apolipoprotein E (Apoe)(-/-) genetic background and fed a high-fat or chow diet. Loss of 1 copy of Zfp148 markedly reduced atherosclerosis without affecting lipid metabolism. Bone marrow transplantation experiments revealed that the effector cell is of hematopoietic origin. Peritoneal macrophages and atherosclerotic lesions from Zfp148(gt/+)Apoe(-/-) mice showed increased levels of phosphorylated p53 compared with controls, and atherosclerotic lesions contained fewer proliferating macrophages. Zfp148(gt/+)Apoe(-/-) mice were further crossed with p53-null mice (Trp53(-/-) [the gene encoding p53]). There was no difference in atherosclerosis between Zfp148(gt/+)Apoe(-/-) mice and controls on a Trp53(+/-) genetic background, and there was no difference in levels of phosphorylated p53 or cell proliferation.
  
  
  CONCLUSIONS
  Zfp148 deficiency increases p53 activity and protects against atherosclerosis by causing proliferation arrest of lesional macrophages, suggesting that drugs targeting macrophage proliferation may be useful in the treatment of atherosclerosis.
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Volkan I
authors.initials: VI
authors.lastname: Sayin
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Omar M
authors.initials: OM
authors.lastname: Khan
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lara E
authors.initials: LE
authors.lastname: Pehlivanoglu
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Staffas
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Mohamed X
authors.initials: MX
authors.lastname: Ibrahim
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Asplund
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Agren
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Nilton
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Bergström
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.affiliation: From the Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine (V.I.S., L.E.P., A.A., P.Å., A.N., G.B., J.B., P.L.), Department of Biochemistry, Institute of Biomedicine (V.I.S., P.L.), and Department of Molecular and Clinical Medicine/Sahlgrenska Cancer Center, Institute of Medicine (O.M.K., A.S., M.X.I., M.O.B.), Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. per.lindahl@wlab.gu.se.
authors.forename: Per
authors.initials: P
authors.lastname: Lindahl
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D006801:Humans; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C110951:ZNF148 protein, human; C491741:Zfp148 protein, mouse
keywords: Zfp148 protein, mouse; atherosclerosis; cell proliferation; genes, p53; macrophages; mice, transgenic