Deletion of Mineralocorticoid Receptors From Macrophages Protects Against Deoxycorticosterone/Salt-Induced Cardiac Fibrosis and Increased Blood Pressure

Abstract

Abstract-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 (MR flox/flox /LysM Cre/Ϫ mice). Male mice from each genotype (MR flox/flox or wild-type and MR flox/flox /LysM Cre/Ϫ mice) were uninephrectomized, given 0.9% NaCl solution to drink, and treated for 8 days or 8 weeks with either vehicle (nϭ10) or deoxycorticosterone (nϭ10). 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 MR flox/flox / LysM Cre/Ϫ mice given deoxycorticosterone. Baseline expression of other inflammatory genes was reduced in MR flox/flox /LysM Cre/Ϫ 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, MR flox/flox /LysMCre/Ϫ 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. T he clinical use of mineralocorticoid receptor (MR) antagonists added to the current standard of care reduces morbidity and mortality in patients with congestive heart failure 1,2 and reduces blood pressure and proteinuria as monotherapy in essential hypertension. 3 Although the precise mechanism for this protection remains to be determined, considerable insights have been obtained from experimental models of mineralocorticoid/salt-mediated cardiac fibrosis 4 -6 ; hypertension, cardiac hypertrophy, and fibrosis are key responses to the administration of aldosterone or deoxycorticosterone (DOC) concurrently with a high salt intake for 8 weeks. Importantly, the pathogenesis of cardiac fibrosis is independent of hypertension and cardiac hypertrophy in this model, suggesting a direct role for MR activation in driving the onset and progression of cardiovascular disease. 4 -6 We and others have previously identified vascular inflammation (ie, osteopontin and plasminogen activator inhibitor type 1 [PA...

Mineralocorticoid Receptor, the Main Player in Aldosterone-Induced Large Artery Stiffness

“…These results suggest that the effect of aldosterone on fibronectin/collagen/elastin content described in other experimental models could be the result of MR activity in other cell types, such as macrophages for instance. 8 In the present study, the increase in α5-integrin expression, in control mice, in response to aldosterone is blunted in NAS-treated MR SMKO mice. Integrins are implicated in the attachment between vascular smooth muscle cells and extracellular matrix.…”

“…For example, specific deletion of MR in mice macrophages showed normal inflammatory cell recruitment in response to deoxycorticosterone/salt treatment but a cardiovascular protection in terms of fibrosis, inflammation, and oxidative stress. 8 Specific deletion of MR in cardiomyocytes improved infarct healing and adverse remodeling after myocardial infarction. 9 In the present issue of Hypertension, Galmiche et al 10 have demonstrated the major implication of MR in large artery remodeling in response to aldosterone.…”

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

“…Given the critical role of monocyte/macrophage MR in promoting macrophage polarization to the proinflammatory M1 phenotype and in the development of cardiac fibrosis in two separate models of hypertension‐induced cardiac remodeling (Rickard et al. 2009; Usher et al. 2010), our data support the notion that EC‐MR does not regulate cardiac fibrosis, but rather that MR in infiltrating leukocytes likely mediates this profibrotic effect.…”

“…Studies using the hypertension model induced with the mouse mineralocorticoid deoxycorticosterone (DOCA) and salt, reported that myeloid cell‐specific MR knockout mice and mice with conditional deletion of MR in both myeloid cells and endothelial cells (EC), were protected from cardiac fibrosis, with the latter model also showing signs of decreased cardiac inflammation (Rickard et al. 2009; Shen et al. 2016).…”

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

“…Although these studies showed that endothelial MR does not contribute to BP regulation, overexpression of MR in the endothelium was found to affect BP 17. MR in myeloid cells and macrophages has roles in cardiac fibrosis and DOCA/salt‐induced BP elevation 18, 19. Vascular smooth muscle cell MR functions in the stiffening of carotid arteries in hypertension induced by an aldosterone/salt challenge20 and in the age‐related increase in BP in mice 21.…”