title: Deletion of progranulin exacerbates atherosclerosis in ApoE knockout mice.
abstract: OBJECTIVE
  Progranulin (PGRN) is a multifunctional protein known to be involved in inflammation. However, the relation between PGRN and atherosclerosis remains elusive. The aim of this study was to define the role of PGRN in the development of atherosclerosis.
  
  
  RESULTS
  First, we checked the expression levels of PGRN in human atherosclerotic plaques. Immunohistochemical analysis showed that PGRN is strongly expressed in foam cells of atherosclerotic plaques. We also found that PGRN is expressed more abundantly in macrophages than in the smooth muscle cells of atherosclerotic lesions in ApoE(-/-) mice fed a high-fat diet for 12 weeks. Next, PGRN(-/-)ApoE(-/-) mice were generated to investigate the effect of PGRN on the development of atherosclerosis. PGRN(-/-)ApoE(-/-) mice exhibited severe atherosclerotic lesions compared with PGRN(+/+)ApoE(-/-) mice, despite their anti-atherogenic lipid profile. These results are partly due to enhanced expression of inflammatory cytokines, adhesion molecules, and decreased expression of endothelial nitric oxide synthase. In addition, lack of PGRN leads to accumulate excessive cholesterol in the macrophages and alter HDL-associated proteins.
  
  
  CONCLUSIONS
  PGRN seems to be involved in the pathogenesis of atherosclerosis, possibly by various anti-atherogenic effects, including modulation of local and/or systemic inflammation.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Kawase
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohama
authors.forename: Akifumi
authors.initials: A
authors.lastname: Matsuyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuwaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Okada
authors.forename: Taiji
authors.initials: T
authors.lastname: Yamashita
authors.forename: Miyako
authors.initials: M
authors.lastname: Yuasa-Kawase
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakaoka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakatani
authors.forename: Miwako
authors.initials: M
authors.lastname: Inagaki
authors.forename: Kazumi
authors.initials: K
authors.lastname: Tsubakio-Yamamoto
authors.forename: Daisaku
authors.initials: D
authors.lastname: Masuda
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nakagawa-Toyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishida
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Ohmoto
authors.forename: Masugi
authors.initials: M
authors.lastname: Nishihara
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Shizuya
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000502:physiology*; D050197:Atherosclerosis / Q000209:etiology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000502:physiology*; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077153:Progranulins
chemical_list: D001057:Apolipoproteins E; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D002784:Cholesterol
keywords: Atherosclerosis; High-density lipoprotein; Inflammation; Macrophage; Progranulin