A major role for RCAN1 in atherosclerosis progression

Authors

  • Nerea Méndez-Barbero,

    1. Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Search for more papers by this author
    • These authors contributed equally to this work.
  • Vanesa Esteban,

    1. Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Search for more papers by this author
    • These authors contributed equally to this work.
  • Silvia Villahoz,

    1. Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Search for more papers by this author
  • Amelia Escolano,

    1. Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Search for more papers by this author
  • Katia Urso,

    1. Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Search for more papers by this author
  • Arantzazu Alfranca,

    1. Human Genetics Department, Institute for Rare Diseases Research, Carlos III Health Institute, Madrid, Spain
    Search for more papers by this author
  • Cristina Rodríguez,

    1. Centro de Investigación Cardiovascular (CSIC-ICCC), Barcelona, Spain
    Search for more papers by this author
  • Susana A. Sánchez,

    1. Microscopy and Dynamic Imaging Unit, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Current affiliation:
    1. Department of polymers, Facultad de Ciencias Quimicas, Universidad de Concepcion, Concepcion, Chile
    Search for more papers by this author
  • Tsuyoshi Osawa,

    1. Division of Vascular Biology, The Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
    Search for more papers by this author
  • Vicente Andrés,

    1. Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Search for more papers by this author
  • José Martínez-González,

    1. Centro de Investigación Cardiovascular (CSIC-ICCC), Barcelona, Spain
    Search for more papers by this author
  • Takashi Minami,

    1. Division of Vascular Biology, The Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
    Search for more papers by this author
  • Juan Miguel Redondo,

    Corresponding author
    1. Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    • Corresponding author: Tel: +34 91 4531200, Ext. 1150; Fax: +34 91 4531265;

      E-mail: jmredondo@cnic.es

      Corresponding author: Tel: +34 91 5854490; Fax: +34 91 5854401;

      E-mail: mcampanero@iib.uam.es

    Search for more papers by this author
    • JMR and MRC contributed equally as corresponding and senior authors.
  • Miguel R. Campanero

    Corresponding author
    1. Department of Cancer Biology, Instituto de Investigaciones Biomedicas Alberto Sols, Madrid, Spain
    • Corresponding author: Tel: +34 91 4531200, Ext. 1150; Fax: +34 91 4531265;

      E-mail: jmredondo@cnic.es

      Corresponding author: Tel: +34 91 5854490; Fax: +34 91 5854401;

      E-mail: mcampanero@iib.uam.es

    Search for more papers by this author
    • JMR and MRC contributed equally as corresponding and senior authors.

Abstract

Atherosclerosis is a complex inflammatory disease involving extensive vascular vessel remodelling and migration of vascular cells. As RCAN1 is implicated in cell migration, we investigated its contribution to atherosclerosis. We show RCAN1 induction in atherosclerotic human and mouse tissues. Rcan1 was expressed in lesional macrophages, endothelial cells and vascular smooth muscle cells and was induced by treatment of these cells with oxidized LDLs (oxLDLs). Rcan1 regulates CD36 expression and its genetic inactivation reduced atherosclerosis extension and severity in Apoe−/− mice. This effect was mechanistically linked to diminished oxLDL uptake, resistance to oxLDL-mediated inhibition of macrophage migration and increased lesional IL-10 and mannose receptor expression. Moreover, Apoe−/−Rcan1−/− macrophages expressed higher-than-Apoe−/− levels of anti-inflammatory markers. We previously showed that Rcan1 mediates aneurysm development and that its expression is not required in haematopoietic cells for this process. However, transplantation of Apoe−/−Rcan1−/− bone-marrow (BM) cells into Apoe−/− recipients confers atherosclerosis resistance. Our data define a major role for haematopoietic Rcan1 in atherosclerosis and suggest that therapies aimed at inhibiting RCAN1 expression or function might significantly reduce atherosclerosis burden.

Ancillary