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Global Translational Medicine Mineralocorticoid receptor in CMD

Figure 3. Role of mineralocorticoid receptor (MR) in vascular cells. In endothelial cells (ECs), MR activation promotes vascular inflammation by
enhancing the expression of surface adhesion molecules, including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and inhibiting
the expression of glucose-6-phosphate dehydrogenase. In addition, MR affects endothelial cell proliferation and migration by inhibiting the expression
of signal transducer and activator of transcription 3 by binding to CCAAT enhancer-binding protein beta. In smooth muscle cells (SMCs), MR regulates
contraction by inhibiting the expression of microRNA-155 and increasing the expression of L-type calcium channel Cav1.2 and angiotensin type-1 receptor.
Moreover, MR activation in SMCs promotes the expression of α5 subunit integrin and aggravates vascular stiffness. On the other hand, MR phosphorylates
and activates non-receptor tyrosine kinases c-Src and mitogen-activated protein kinase (MAPK), thereby leading to vascular inflammation, oxidative
stress, proliferation and migration of SMCs, and extracellular matrix deposition. In fibroblasts, MR activation promotes proliferation of fibroblasts by
activating Ki-RasA and MAPK1/2 signaling as well as increasing cyclin D1 and E2 expression.

MR antagonists have opposite effects on angiogenesis have shown that EC-specific MR knockout does not affect
in different models of diseases. Eplerenone, a selective glucose tolerance or inflammation in white adipose tissue
MR antagonist, has shown to promote angiogenesis in but prevents endothelial dysfunction in obese animals .
[74]
rat hindlimb ischemia by improving the proliferation Similarly, EC MR deficiency has shown to improve endothelial
and function of endothelial progenitor cells . However, dysfunction, vascular stiffness, and cardiac diastolic
[71]
Zhao et al. have reported that treatment with another MR dysfunction in western diet (WD)-induced obesity and
antagonist spironolactone reduces symptoms of choroidal T2DM female mice, without affecting the body composition
neovascularization (CNV) in patients with age-related or insulin sensitivity of mice fed WD [75,76] . Mechanistically,
macular degeneration (AMD) . Furthermore, in a rodent EC MR deletion ameliorates WD-induced aortic fibrosis and
[72]
model of AMD, MR antagonist or specific deletion of MR stiffness by inhibiting the endothelial expression of sodium
in ECs has shown to exert anti-angiogenic effects, partially channels, oxidative stress, and macrophage polarization, as
through the upregulation of decorin expression . These well as enhancing the endothelial activation of nitric oxide
[72]
experimental results suggest that endothelial MR regulates (NO) synthase . These results provide clear evidence that
[76]
angiogenesis differentially in different types of vessels and EC MR contributes to endothelial dysfunction and vascular
disease models. stiffness in obesity and diabetes.

3.1.4. Role of endothelial cell MR in obesity and 3.1.5. Role of endothelial cell MR in pulmonary
diabetes arterial hypertension (PAH)
Clinical studies have provided evidence to support a link PAH is a syndrome characterized by a progressive
between MR and vascular dysfunction in obese patients . increase in pulmonary vascular load and significant
[73]
Hwang et al. have found that eplerenone improves vascular pulmonary vascular remodeling . Increased pulmonary
[77]
endothelial function in older adults, especially those with artery resistance leads to right ventricle remodeling and
more total body fat and abdominal fat . The previous studies failure [77,78] . The previous studies have reported that plasma
[73]
Volume 2 Issue 1 (2023) 6 https://doi.org/10.36922/gtm.v2i1.229