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Global Translational Medicine Mineralocorticoid receptor in CMD

trials have shown that the activation of aldosterone/MR the recruitment of immune cells, both of which contribute
signaling increases the risk and adverse clinical outcomes to tissue damage and impaired healing in CMDs .
[30]
in patients with hypertension, myocardial infarction MR is expressed in most immune cells, including
(MI), heart failure (HF), and stroke [10,11] . Experimental monocytes/macrophages, dendritic cells (DCs), T cells, and
evidence has demonstrated that MR activation by B cells . Immune cell MR is involved in the pathological
[30]
aldosterone induces oxidative stress, inflammation, processes of many cardiovascular and metabolic diseases.
and fibrosis, all of which contribute to the progression
of CMDs [12,13] . However, aldosterone is not the only 2.1. Macrophage MR and CMDs
ligand for MR. Glucocorticoids have similar affinity and 2.1.1. Role of macrophage MR in atherosclerosis
specificity for MR . In certain cells, 11β-hydroxysteroid
[14]
dehydrogenase type 2 (11β-HSD2) restricts the binding Macrophages are the main immune cells in atherosclerotic
of glucocorticoids to MR by converting endogenous plaques and are closely related to the pathological process of
[31]
glucocorticoids to metabolites that have poor affinity atherosclerosis . MR activation by aldosterone increases
for MR . Conversely, the enzyme 11β-hydroxysteroid atherosclerosis plaque size and macrophage numbers in
[7]
[32]
dehydrogenase type 1 (11β-HSD1) converts the inactive the plaques . Conversely, MR inactivation by eplerenone
dehydrogenated form of glucocorticoids into active decreases macrophage oxidative stress and improves
[33]
form [7,15] . The ligand-independent activation of MR has atherosclerosis . Recent studies have suggested that
[34,35]
also been investigated. Rac1, a small GTPase belonging macrophage MR plays a major role in atherosclerosis .
to the Rho family, can activate MR, leading to nuclear MR deficiency in macrophages decreases plaque size in
translocation in renal and cardiac diseases [16,17] . It has been early- and late-stage atherosclerosis through different
reported that high glucose activates the transcriptional mechanisms. In the early stage of atherogenesis, MR
activity of MR through protein kinase C β signaling and deficiency downregulates the expression of P-selectin
[18]
high salt causes renal MR activation through the induction glycoprotein ligand-1 (a critical mediator of leukocyte
of oxidative stress and exacerbates renal injury . rolling) in macrophages and suppresses leukocyte
[19]
trafficking to reduce inflammation in atherosclerotic
It has been clearly established that MR is expressed and plaques . Macrophage-specific MR deletion inhibits
[35]
functional in extra-renal tissues, such as brain, liver, lung, macrophage foam cell formation and increases the
colon, bone, heart, vasculature, and immune system [20,21] . phagocytic and efferocytosis capacities of macrophages in
The role of MR varies in different cell types. For example, a mouse model of late-stage atherosclerosis .
[34]
monocyte/macrophage MR deficiency affects macrophage
polarization and vascular remodeling [22,23] . The deletion 2.1.2. Role of macrophage MR in MI
of vascular smooth muscle MR ameliorates aging- or Macrophage MR deficiency has been shown to improve
angiotensin (Ang) II-induced hypertension in mice . cardiac function and decrease the size of infarct scar
[24]
Although the overexpression of MR in endothelial cells following MI, with enhanced infarct neovascularization
promotes vasoconstriction and leads to hypertension , and scar maturation . Mechanistically, MR deletion
[25]
[36]
the deletion of MR has no effect on blood pressure [25,26] . in macrophages promotes post-MI cardiac repair by
MR knockout in T cells alleviates renal and vascular lesions enhancing neutrophil efferocytosis, suppressing free
and reduces Ang II-induced hypertension . Therefore, radical formation, and regulating fibroblast activation
[27]
elucidating the regulatory mechanisms of MR in different status . Targeting macrophages with eplerenone-
[36]
cell types may provide new strategies to treat CMDs.
containing liposome protects against cardiac dysfunction
This review summarizes the effects of MR in different and adverse cardiac remodeling following MI, thus
cell types on the pathological process of CMDs and suggesting that the targeted delivery of MR antagonists to
specifically highlights the expression and function of MR macrophages post-MI could be a novel strategy to prevent
in immune cells, adipocytes, vascular cells, and myocardial the side effects of MR antagonists on electrolytes .
[36]
cells. We also discuss the application and challenges of
MR antagonists in the treatment of CMDs, to highlight 2.1.3. Role of macrophage MR in hypertension
promising novel therapeutic strategies. The role of macrophage MR has also been investigated
in different models of hypertension [22,37,38] . In
2. Immune cell MR and CMDs deoxycorticosterone acetate (DOCA)/salt- and low-dose
Inflammation and immune cells are closely related to the treatment of N -nitro-L-arginine methyl ester (L-NAME)/
G
pathogenesis of CMDs [5,28-30] . The previous studies have salt-induced hypertension models, the deletion of
shown that aldosterone activates the immune system to macrophage MR reduces systolic blood pressure, diminishes
promote the expression of inflammatory cytokines and cardiac fibrosis, and inhibits the expression of pro-

Volume 2 Issue 1 (2023) 2 https://doi.org/10.36922/gtm.v2i1.229