CCL2-dependent macrophage recruitment is critical for mineralocorticoid receptor-mediated cardiac fibrosis, inflammation, and blood pressure responses in male mice

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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.
Original languageEnglish
Pages (from-to)1057 - 1066
Number of pages10
Issue number3
Publication statusPublished - 2014

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