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Title: | CCL2-dependent macrophage recruitment is critical for mineralocorticoid receptor-mediated cardiac fibrosis, inflammation, and blood pressure responses in male mice. | Authors: | Young M.J.;Fuller P.J.;Tesch G.H.;Morgan J.;Shen J.Z. | Institution: | (Shen, Morgan, Fuller, Young) Prince Henry's Institute of Medical Research, P.O. Box 5152, Clayton, VIC 3168, Australia (Shen, Tesch, Fuller, Young) Department of Medicine, Monash University, Clayton, VIC 3168, Australia (Young) Department of Physiology, Monash University, Clayton, VIC 3168, Australia (Tesch) Department of Nephrology, Monash Medical Centre, Clayton, VIC 3168, Australia | Issue Date: | 12-Mar-2014 | Copyright year: | 2014 | Publisher: | Endocrine Society (8401 Connecticut Ave. Suite 900, Chevy Chase MD 20815, United States) | Place of publication: | United States | Publication information: | Endocrinology. 155 (3) (pp 1057-1066), 2014. Date of Publication: March 2014. | Abstract: | Recent studies show that mice with selective deletion of the mineralocorticoid receptor (MR) in macrophages are protected from mineralocorticoid-induced cardiac fibrosis and hypertension without altering cardiac macrophage accumulation. However, it is unclear whether preventing macrophages from entering cardiac tissue would provide similar or additional protection in this disease setting. Therefore, we examined mineralocorticoid- induced cardiovascular disease in mice lacking the CCL2 gene (encoding monocyte chemoattractant protein-1), which have a markedly reduced capacity to recruit proinflammatory tissue macrophages. Male wild-type (WT) and CCL2-null mice were treated for 8 days or 8 weeks with either vehicle (control, CON) or deoxycorticosterone (DOC). At both time points, there was a significant reduction in DOC-induced macrophage recruitment (50% at 8 d and 75% at 8 wk) in the heart with a corresponding suppression of cardiac inflammatory markers in the CCL2-null mice. CCL2-null mice given DOC/salt also displayed 35% less cardiac fibrosis at 8 weeks vs WT DOC. Absence of recruited macrophages in CCL2-null mice promotes greater collagen breakdown by matrix metalloproteinase-9 in the heart and also leads to significantly reduced cardiac fibroblast and myofibroblast numbers. Systolic blood pressure (BP) after DOC/salt was significantly lower in CCL2-null than for WT mice. In the aorta at 8 weeks, MR-responsive gene expression remained intact. However, macrophage-mediated proinflammatory gene expression was reduced in the CCL2-null mice and may account for differential regulation of BP. Our data thus demonstrate an important role for CCL2-dependent macrophage recruitment in MR-dependent cardiac inflammation and remodeling and in the regulation of systolic BP. Copyright © 2014 by the Endocrine Society. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1210/en.2013-1772 | Link to associated publication: | Click here for full text options | PubMed URL: | 24428529 [http://www.ncbi.nlm.nih.gov/pubmed/?term=24428529] | ISSN: | 0013-7227 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/41790 | Type: | Article | Subjects: | heart weight hypertension/et [Etiology] immunohistochemistry inflammatory cell intracellular signaling *macrophage male mouse myofibroblast nonhuman priority journal *systolic blood pressure wild type aldosterone/ec [Endogenous Compound] alpha smooth muscle actin/ec [Endogenous Compound] angiotensin II/ec [Endogenous Compound] brain natriuretic peptide/ec [Endogenous Compound] calvasculin/ec [Endogenous Compound] CD3 antigen/ec [Endogenous Compound] cell marker/ec [Endogenous Compound] chemokine receptor CCR5/ec [Endogenous Compound] chlordane/ec [Endogenous Compound] collagen/ec [Endogenous Compound] connective tissue growth factor/ec [Endogenous Compound] corticosterone/ec [Endogenous Compound] deoxycorticosterone endothelin 1/ec [Endogenous Compound] gelatinase A/ec [Endogenous Compound] gelatinase B/ec [Endogenous Compound] incyclinide/ec [Endogenous Compound] interleukin 23/ec [Endogenous Compound] *mineralocorticoid receptor *monocyte chemotactic protein 1/ec [Endogenous Compound] osteopontin/ec [Endogenous Compound] plasminogen activator inhibitor 1/ec [Endogenous Compound] platelet derived growth factor beta receptor/ec [Endogenous Compound] RANTES/ec [Endogenous Compound] Rho guanine nucleotide dissociation inhibitor 2/ec [Endogenous Compound] transforming growth factor beta1/ec [Endogenous Compound] tumor necrosis factor alpha fibroblast aldosterone blood level angiotensin blood level animal experiment animal model animal tissue article *cardiovascular inflammation/et [Etiology] CD3+ T lymphocyte cell infiltration controlled study corticosterone blood level enzyme activity gene expression gene inactivation *heart muscle fibrosis/et [Etiology] heart ventricle hypertrophy corticosterone blood level enzyme activity fibroblast gene expression gene inactivation *heart muscle fibrosis / *etiology heart ventricle hypertrophy heart weight hypertension / etiology immunohistochemistry inflammatory cell intracellular signaling *macrophage male mouse myofibroblast nonhuman angiotensin blood level *systolic blood pressure wild type aldosterone blood level priority journal animal experiment animal model animal tissue article *cardiovascular inflammation / *etiology CD3+ T lymphocyte cell infiltration controlled study |
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