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    Macrophage Mineralocorticoid Receptor Signaling Plays a Key Role in Aldosterone-Independent Cardiac Fibrosis

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    Author
    Bienvenu, LA; Morgan, J; Rickard, AJ; Tesch, GH; Cranston, GA; Fletcher, EK; Delbridge, LMD; Young, MJ
    Date
    2012-07-01
    Source Title
    ENDOCRINOLOGY
    Publisher
    ENDOCRINE SOC
    University of Melbourne Author/s
    Delbridge, Leanne; Bienvenu, Laura
    Affiliation
    Physiology
    Metadata
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    Document Type
    Journal Article
    Citations
    Bienvenu, L. A., Morgan, J., Rickard, A. J., Tesch, G. H., Cranston, G. A., Fletcher, E. K., Delbridge, L. M. D. & Young, M. J. (2012). Macrophage Mineralocorticoid Receptor Signaling Plays a Key Role in Aldosterone-Independent Cardiac Fibrosis. ENDOCRINOLOGY, 153 (7), pp.3416-3425. https://doi.org/10.1210/en.2011-2098.
    Access Status
    This item is currently not available from this repository
    URI
    http://hdl.handle.net/11343/32835
    DOI
    10.1210/en.2011-2098
    Description

    C1 - Journal Articles Refereed

    Abstract
    Mineralocorticoid receptor (MR) activation promotes the development of cardiac fibrosis and heart failure. Clinical evidence demonstrates that MR antagonism is protective even when plasma aldosterone levels are not increased. We hypothesize that MR activation in macrophages drives the profibrotic phenotype in the heart even when aldosterone levels are not elevated. The aim of the present study was to establish the role of macrophage MR signaling in mediating cardiac tissue remodeling caused by nitric oxide (NO) deficiency, a mineralocorticoid-independent insult. Male wild-type (MRflox/flox) and macrophage MR-knockout (MRflox/flox/LysMCre/+; mac-MRKO) mice were uninephrectomized, maintained on 0.9% NaCl drinking solution, with either vehicle (control) or the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (L-NAME; 150 mg/kg/d) for 8 wk. NO deficiency increased systolic blood pressure at 4 wk in wild-type L-NAME/salt-treated mice compared with all other groups. At 8 wk, systolic blood pressure was increased above control in both L-NAME/salt treated wild-type and mac-MRKO mice by approximately 28 mm Hg by L-NAME/salt. Recruitment of macrophages was increased 2- to 3-fold in both L-NAME/salt treated wild-type and mac-MRKO. Inducible NOS positive macrophage infiltration and TNFα mRNA expression was greater in wild-type L-NAME/salt-treated mice compared with mac-MRKO, demonstrating that loss of MR reduces M1 phenotype. mRNA levels for markers of vascular inflammation and oxidative stress (NADPH oxidase 2, p22phox, intercellular adhesion molecule-1, G protein-coupled chemokine receptor 5) were similar in treated wild-type and mac-MRKO mice compared with control groups. In contrast, L-NAME/salt treatment increased interstitial collagen deposition in wild-type by about 33% but not in mac-MRKO mice. mRNA levels for connective tissue growth factor and collagen III were also increased above control treatment in wild-type (1.931 ± 0.215 vs. 1 ± 0.073) but not mac-MRKO mice (1.403 ± 0.150 vs. 1.286 ± 0.255). These data demonstrate that macrophage MR are necessary for the translation of inflammation and oxidative stress into interstitial and perivascular fibrosis after NO deficiency, even when plasma aldosterone is not elevated.
    Keywords
    Cardiology (incl. Cardiovascular Diseases); Cardiovascular System and Diseases

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