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CC chemokine receptor 5 influences late-stage atherosclerosis

  • Author Footnotes
    1 These authors contributed equally to this study.
    Marlon P. Quinones
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, United States

    Departments of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, United States

    Veterans Administration Center for Research on AIDS and HIV-1 Infection, San Antonio, TX, United States
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this study.
    Hernan G. Martinez
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, United States

    Departments of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, United States

    Veterans Administration Center for Research on AIDS and HIV-1 Infection, San Antonio, TX, United States
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this study.
    Fabio Jimenez
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, United States

    Departments of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, United States

    Veterans Administration Center for Research on AIDS and HIV-1 Infection, San Antonio, TX, United States
    Search for articles by this author
  • Carlos A. Estrada
    Affiliations
    South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, United States

    Departments of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, United States

    Veterans Administration Center for Research on AIDS and HIV-1 Infection, San Antonio, TX, United States
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  • Molly Dudley
    Affiliations
    South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, United States

    Departments of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, United States

    Veterans Administration Center for Research on AIDS and HIV-1 Infection, San Antonio, TX, United States
    Search for articles by this author
  • Opal Willmon
    Affiliations
    South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, United States

    Departments of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, United States

    Veterans Administration Center for Research on AIDS and HIV-1 Infection, San Antonio, TX, United States
    Search for articles by this author
  • Hemant Kulkarni
    Affiliations
    South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, United States

    Departments of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, United States

    Veterans Administration Center for Research on AIDS and HIV-1 Infection, San Antonio, TX, United States
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  • Robert L. Reddick
    Affiliations
    Departments of Pathology, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, United States
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  • Gabriel Fernandes
    Affiliations
    Departments of Pathology, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, United States
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  • William A. Kuziel
    Affiliations
    Protein Design Labs, Inc., Fremont, CA 94555, United States
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  • Author Footnotes
    1 These authors contributed equally to this study.
    Sunil K. Ahuja
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, United States

    Departments of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, United States

    Veterans Administration Center for Research on AIDS and HIV-1 Infection, San Antonio, TX, United States
    Search for articles by this author
  • Seema S. Ahuja
    Correspondence
    Corresponding author at: Department of Medicine (MC 7870), University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, United States. Tel.: +1 210 567 4691; fax: +1 210 567 4654.
    Affiliations
    South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, United States

    Departments of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, United States

    Veterans Administration Center for Research on AIDS and HIV-1 Infection, San Antonio, TX, United States
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this study.

      Abstract

      Members of the chemokine system, play a central role in inflammatory processes that underlie the pathogenesis of atherosclerosis and possibly, aortic valve sclerosis. Here we show that genetic inactivation of CC chemokine receptor 5 (CCR5) in the atherosclerosis-prone Apoe−/− mice (Apoe−/−Ccr5−/−) fed a normal chow or a high-fat diet (HFD) are protected against advanced atherosclerosis as well as age-associated aortic valve thickening (AAAVT)—a murine correlate of aortic valve sclerosis. Notably, human sclerotic valves contained CCR5+ cells. We confirm that Apoe−/−Ccr5−/− mice does not influence early-atherosclerotic stage. Adoptive transfer studies showed that the atheroprotective effect of CCR5 inactivation resided in the bone marrow compartment, but was not dependent on T-cells. The CCR5-null state was associated with phenotypes postulated to be atheroprotective such as reduced macrophage accumulation in the plaque, and lower circulating levels of IL-6 and MCP-5. The lack of CCR5 expression in Apoe−/− mice was also associated with higher numbers of endothelial progenitor cells (EPCs)—another postulated athero-protective factor. Compared with controls, carriers of a polymorphism in the Ccr5 gene that leads to the lack of CCR5 in the cell surface had an increased mean percentage of EPCs, but this difference did not reach statistical significance. Collectively, these findings underscore a critical role of CCR5 in age-associated cardiovascular diseases, and highlight that the effects of the chemokine system can be temporally constrained to distinct stages of these disease processes.

      Abbreviations:

      AAAVT (age-associated aortic valve thickening), BM (bone marrow), CAD (coronary artery disease), CCR5 (CC chemokine receptor 5), CX3CR1 (C-X3-C-motif chemokine receptor 1), EPCs (endothelial progenitor cells), GFP (green fluorescent protein), HFD (high-fat diet), IL (interleukin), MCP-5 (monocyte chemoattractant protein-5), ND (normal diet)

      Keywords

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