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Global Translational Medicine Mineralocorticoid receptor in CMD

aldosterone levels are elevated in animal models and in hand, SMC-specific MR deletion ameliorates vascular
patients with PAH, implying that MR signaling may be stiffness in aldosterone/salt-induced hypertensive mouse
involved in the pathophysiological process of PAH [79-81] . model with decreased expression of α5-subunit integrin
[86]
Moreover, treatment with spironolactone or eplerenone (Figure 3). Lu et al. have found that in SMCs, Ang II acts
attenuates pulmonary vascular remodeling without affecting through angiotensin type 1 receptors to phosphorylate
the structure and function of the right ventricle in animal and activate the δ isoform of protein kinase C, which
models of PAH [82,83] , suggesting that the main protective role in turn activates the transcriptional activity of MR and
of MR antagonists is related to pulmonary vessels. In a recent subsequently promotes the expression of MR target genes
study, Kowalski et al. corroborated previous observations as well as the proliferation of SMCs .
[88]
that MR antagonists alleviate pulmonary arteriole
remodeling and right ventricular hypertrophy through a 3.2.2. Role of SMC MR in MI and HF
mouse model of hypoxia-induced PAH . Surprisingly, The role of SMC MR in MI has also been investigated. It has
[84]
MR deletion in ECs attenuates hypoxia-induced PAH and been demonstrated that MR deletion in SMCs improves
right ventricular failure, but its deletion in smooth muscle coronary and left ventricular (LV) dysfunction in mouse
cells (SMCs), fibroblasts, or myeloid cells does not have MI model . Mechanistically, SMC-specific MR deficiency
[89]
any significant effect . Meanwhile, EC MR deficiency has exerts a protective role in post-MI hearts by improving LV
[84]
shown to inhibit pulmonary arteriole remodeling and right compliance and elastance as well as reducing interstitial
ventricular hypertrophy, thus recapitulating the beneficial fibrosis and oxidative stress . However, the LV ejection
[89]
effects observed in eplerenone treatment . Mechanistically, fraction, LV mass, and heart infarct sizes have been
[84]
MR deletion in ECs attenuates the expression of genes related shown to be similar between SMC MR knockout mice
to blood pressure and Notch signaling pathway regulation and control mice after MI. MR blockage by finerenone
[84]
in hypoxia-treated primary pulmonary ECs . Of note, MR (nonsteroidal MR antagonists) has shown similar
deficiency inhibits the upregulation of endothelin-converting effects as well as . These results support that SMC MR
[89]
enzyme 1 and endothelin receptor B, which are both elevated contributes to coronary and left LV dysfunction after
in response to hypoxic stimulation . However, further MI. Recent animal experiments have suggested that SMC
[84]
investigation is needed to determine if the low expression MR deletion exerts protective effect on transverse aortic
of endothelin-converting enzyme 1 and endothelin receptor constriction (TAC)-induced HF with markedly improved
B in MR-deficient ECs improves pulmonary vascular ejection fraction, cardiac stiffness, ventricular dimensions,
remodeling. Moreover, SMCs, fibroblasts, and inflammatory intracardiac pressure, pulmonary edema, and exercise
cells are also involved in pulmonary arterial remodeling in capacity . Mechanistically, MR deletion in SMCs protects
[90]
PAH. However, only EC MR deletion can improve the PAH cardiac function and adverse cardiac remodeling by
phenotype, suggesting the existence of a crosstalk between alleviating cardiomyocyte hypertrophy, inhibiting cardiac
endothelial and other cell types. More studies are needed to interstitial and perivascular fibrosis, reducing myocardial
understand the detailed molecular mechanisms. inflammation, as well as increasing cardiac capillary
[90]
3.2. Role of MR in SMCs density and coronary blood flow reserve .
3.2.1. Role of SMC MR in hypertension 3.3. Role of MR in fibroblasts
SMCs regulate blood pressure by modulating Fibroblasts are the most important source of cardiac
vasoconstriction . It has been proposed that uncontrolled extracellular matrix (ECM), and they play an important
[85]
proliferating SMCs account for media thickening role in the pathogenesis of MI, hypertension, and
[91]
and vascular stiffness in the pathological process of HF . It has been reported that MR is expressed in
hypertension . The importance of MR in SMCs for blood fibroblasts . In vitro studies have verified the direct role
[92]
[85]
pressure regulation has been widely reported [24,86,87] . Studies of MR in cardiac fibroblasts. Stockand and Meszaros have
in mouse model have demonstrated that SMC-specific MR demonstrated that aldosterone is able to stimulate cardiac
deficiency lowers blood pressure in both aged mice and fibroblast proliferation through the activation of Ki-RasA
high sodium-induced hypertensive mice [24,86] . Meanwhile, and mitogen-activated protein kinase (MAPK)1/2
[93]
SMC-specific MR knockout mice have shown improved signaling (Figure 3). This conclusion is supported by the
contractile function and anti-oxidative stress response to findings of another experiment, showing that aldosterone
Ang II . Mechanistically, MR regulates SMC contraction promotes rat cardiac fibroblast proliferation by increasing
[24]
[94]
by inhibiting the expression of microRNA-155 and cyclin D1 and cyclin E2 expression (Figure 3). These
increasing the expression of L-type calcium channel Cav1.2 findings suggest that aldosterone-induced MR activation
and angiotensin type-1 receptor (Figure 3). On the other promotes cardiac fibroblast proliferation in vitro. Whether
[87]
Volume 2 Issue 1 (2023) 7 https://doi.org/10.36922/gtm.v2i1.229