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Reducing macrophage proteoglycan sulfation increases atherosclerosis and obesity through enhanced type I interferon signaling.
Gordts, Philip L S M; Foley, Erin M; Lawrence, Roger; Sinha, Risha; Lameda-Diaz, Carlos; Deng, Liwen; Nock, Ryan; Glass, Christopher K; Erbilgin, Ayca; Lusis, Aldons J; Witztum, Joseph L; Esko, Jeffrey D.
Afiliação
  • Gordts PLSM; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Foley EM; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
  • Lawrence R; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Sinha R; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Lameda-Diaz C; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Deng L; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Nock R; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Glass CK; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Erbilgin A; Department of Cardiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Lusis AJ; Department of Cardiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Witztum JL; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Esko JD; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jesko@ucsd.edu.
Cell Metab ; 20(5): 813-826, 2014 Nov 04.
Article em En | MEDLINE | ID: mdl-25440058
ABSTRACT
Heparan sulfate proteoglycans (HSPGs) are an important constituent of the macrophage glycocalyx and extracellular microenvironment. To examine their role in atherogenesis, we inactivated the biosynthetic gene N-acetylglucosamine N-deacetylase-N-sulfotransferase 1 (Ndst1) in macrophages and crossbred the strain to Ldlr(-/-) mice. When placed on an atherogenic diet, Ldlr(-/-)Ndst1(f/f)LysMCre(+) mice had increased atherosclerotic plaque area and volume compared to Ldlr(-/-) mice. Diminished sulfation of heparan sulfate resulted in enhanced chemokine expression; increased macrophages in plaques; increased expression of ACAT2, a key enzyme in cholesterol ester storage; and increased foam cell conversion. Motif analysis of promoters of upregulated genes suggested increased type I interferon signaling, which was confirmed by elevation of STAT1 phosphorylation induced by IFN-ß. The proinflammatory macrophages derived from Ndst1(f/f)LysMCre(+) mice also sensitized the animals to diet-induced obesity. We propose that macrophage HSPGs control basal activation of macrophages by maintaining type I interferon reception in a quiescent state through sequestration of IFN-ß.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Interferon Tipo I / Proteoglicanas de Heparan Sulfato / Aterosclerose / Macrófagos / Obesidade Limite: Animals Idioma: En Ano de publicação: 2014 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Interferon Tipo I / Proteoglicanas de Heparan Sulfato / Aterosclerose / Macrófagos / Obesidade Limite: Animals Idioma: En Ano de publicação: 2014 Tipo de documento: Article