Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure
AJ Rickard, J Morgan, G Tesch, JW Funder… - …, 2009 - Am Heart Assoc
Increased mineralocorticoid levels plus high salt promote vascular inflammation and cardiac
tissue remodeling. Mineralocorticoid receptors are expressed in many cell types of the
cardiovascular system, including monocytes/macrophages and other inflammatory cell
types. Although mineralocorticoid receptors are expressed in monocytes/macrophages, their
role in regulating macrophage function to date has not been investigated. We, thus, used the
Cre/LoxP-recombination system to selectively delete mineralocorticoid receptors from …
tissue remodeling. Mineralocorticoid receptors are expressed in many cell types of the
cardiovascular system, including monocytes/macrophages and other inflammatory cell
types. Although mineralocorticoid receptors are expressed in monocytes/macrophages, their
role in regulating macrophage function to date has not been investigated. We, thus, used the
Cre/LoxP-recombination system to selectively delete mineralocorticoid receptors from …
Increased mineralocorticoid levels plus high salt promote vascular inflammation and cardiac tissue remodeling. Mineralocorticoid receptors are expressed in many cell types of the cardiovascular system, including monocytes/macrophages and other inflammatory cell types. Although mineralocorticoid receptors are expressed in monocytes/macrophages, their role in regulating macrophage function to date has not been investigated. We, thus, used the Cre/LoxP-recombination system to selectively delete mineralocorticoid receptors from monocytes/macrophages with the lysozyme M promoter used to drive Cre expression (MRflox/flox/LysMCre/− mice). Male mice from each genotype (MRflox/flox or wild-type and MRflox/flox/LysMCre/− mice) were uninephrectomized, given 0.9% NaCl solution to drink, and treated for 8 days or 8 weeks with either vehicle (n=10) or deoxycorticosterone (n=10). Equivalent tissue macrophage numbers were seen for deoxycorticosterone treatment of each genotype at 8 days; in contrast, plasminogen activator inhibitor type 1 and NAD(P)H oxidase subunit 2 levels were increased in wild-type but not in MRflox/flox/LysMCre/− mice given deoxycorticosterone. Baseline expression of other inflammatory genes was reduced in MRflox/flox/LysMCre/− mice compared with wild-type mice. At 8 weeks, deoxycorticosterone-induced macrophage recruitment and connective tissue growth factor and plasminogen activator inhibitor type 1 mRNA levels were similar for each genotype; in contrast, MRflox/flox/LysMCre/− mice showed no increase in cardiac fibrosis or blood pressure, as was seen in wild-type mice at 8 weeks. These data demonstrate the following points: (1) mineralocorticoid receptor signaling regulates basal monocyte/macrophage function; (2) macrophage recruitment is not altered by loss of mineralocorticoid receptor signaling in these cells; and (3) a novel and significant role is seen for macrophage signaling in the regulation of cardiac remodeling and systolic blood pressure in the deoxycorticosterone/salt model.
Am Heart Assoc