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Loss of One Copy of Zfp148 Reduces Lesional Macrophage Proliferation and Atherosclerosis in Mice by Activating p53

Journal article
Authors Volkan I. Sayin
Omar M. Khan
Lara Pehlivanoglu
Anna Staffas
Mohamed X Ibrahim
Annika Asplund
Pia Ågren
Anna Nilton
Göran Bergström
Martin Bergö
Jan Borén
Per Lindahl
Published in Circulation Research
Volume 115
Issue 9
Pages 781-791
ISSN 0009-7330
Publication year 2014
Published at Wallenberg Laboratory
Sahlgrenska Cancer Center
Institute of Biomedicine
Pages 781-791
Language en
Links dx.doi.org/10.1161/circresaha.115.3...
Keywords atherosclerosis, cell proliferation, genes, p53, macrophages, mice, transgenic, Zfp148 protein, mouse, TRANSCRIPTION FACTOR ZBP-89, GENE-EXPRESSION, LOCAL PROLIFERATION, CELL-PROLIFERATION, DEFICIENCY LEADS, KNOCKOUT MICE, IN-VIVO, APOPTOSIS, INFLAMMATION, RECRUITMENT, Cardiac & Cardiovascular Systems, Hematology, Peripheral Vascular, Disease
Subject categories Cardiac and Cardiovascular Systems

Abstract

Rationale: 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. Methods and 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.

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