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

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.

Cardiomyocyte Mineralocorticoid Receptors Are Essential for Deoxycorticosterone/Salt-Mediated Inflammation and Cardiac Fibrosis

“…Previously, the MR has been shown to regulate leukocyte adhesion on endothelial cells 5 and to promote a proinflammatory macrophage phenotype 29 ; our data show that the cardiomyocyte MR regulates multiple stages of the DOC/salt inflammatory and fibrotic cardiac responses. The early responses to DOC/salt are suppressed in MR-null cardiomyocytes, which may be translated into a loss of the expanded tissue inflammatory response at 8 weeks and abrogation of tissue fibrosis.…”

Myeloid Mineralocorticoid Receptor Activation Contributes to Progressive Kidney Disease

“…In comparison, studies in models of CVD and cerebral ischemia have shown that MyMRKO mice have reduced levels of M1 cytokines and that this can occur with and without a reduction in macrophage numbers. 15,16,19 Notably, some of these in vivo studies and experiments using cultured cells have indicated that a deficiency of MR signaling in macrophages can alter macrophage gene expression toward an M2 alternatively activated phenotype. 15,16 Our PCR analysis of CD11b + macrophages isolated from WT and MyMRKO kidneys at day 15 of disease found no difference in the M1/M2 phenotype.…”

Overnutrition, mTOR signaling, and cardiovascular diseases

“…Studies employing deletion of MR from specific cell types in mice suggest macrophage MRs play a key role in modulating macrophage polarization and promoting cardiac hypertrophy, inflammation, and fibrosis (10,11,51,79). Loss of MR in macrophage-MR knockout (KO) mice results in reduction in M1 phenotype and mRNA levels for markers of vascular inflammation (10).…”