30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature

DuPont, Jennifer J.; Jaffe, Iris Z.

doi:10.1530/joe-17-0009

Cited by 80 publications

(46 citation statements)

References 114 publications

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“…Indeed, we show in the present study that depressed patients had higher glucose levels and lower HDL cholesterol values than healthy controls. Increased aldosterone is an established risk factor for mortality in CVD, and blocking MR has beneficial effects on many CVD endpoints, including mortality 69,70 . Several prospective studies in different populations have shown that higher cortisol values are associated with cardiovascular mortality [71][72][73] .…”

Section: Discussionmentioning

confidence: 99%

Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression

et al. 2020

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Major depressive disorder (MDD) is associated with altered mineralocorticoid receptor (MR) and glucocorticoid receptor function, and disturbed glutamatergic signaling. Both systems are closely intertwined and likely contribute not only to the pathophysiology of MDD, but also to the increased cardiovascular risk in MDD patients. Less is known about other steroid hormones, such as aldosterone and DHEA-S, and how they affect the glutamatergic system and cardiovascular disease risk in MDD. We examined salivary cortisol, aldosterone, and DHEA-S secretion after stimulation of MR and glutamatergic NMDA receptors in 116 unmedicated depressed patients, and 116 age-and sex-matched healthy controls. Patients (mean age = 34.7 years, SD = ±13.3; 78% women) and controls were randomized to four conditions: (a) control condition (placebo), (b) MR stimulation (0.4 mg fludrocortisone), (c) NMDA stimulation (250 mg D-cycloserine (DCS)), and (d) combined MR/NMDA stimulation (fludrocortisone + DCS). We additionally determined the cardiovascular risk profile in both groups. DCS had no effect on steroid hormone secretion, while cortisol secretion decreased in both fludrocortisone conditions across groups. Independent of condition, MDD patients showed (1) increased cortisol, increased aldosterone, and decreased DHEA-S concentrations, and (2) increased glucose levels and decreased high-density lipoprotein cholesterol levels compared with controls. Depressed patients show profound alterations in several steroid hormone systems that are associated both with MDD pathophysiology and increased cardiovascular risk. Prospective studies should examine whether modulating steroid hormone levels might reduce psychopathology and cardiovascular risk in depressed patients.

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Section: Discussionmentioning

confidence: 99%

Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression

et al. 2020

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“…Mineralocorticoid receptor (MR) is a classic nuclear receptor and its antagonists have been used to treat patients with heart failure or resistant hypertension . MR in ECs has been shown to play important roles in cardiovascular homeostasis and pathogenesis . An endothelial MR‐deficient mouse has been created and used to demonstrate the importance of endothelial MR in the regulation of vascular dysfunction, remodeling, inflammation, and oxidative stress , as well as cardiac dysfunction, remodeling, inflammation, and oxidative stress .…”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoid receptor negatively regulates angiogenesis through repression of STAT3 activity in endothelial cells

Zheng

Liu

Zhang

et al. 2019

The Journal of Pathology

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The mineralocorticoid receptor (MR) plays important roles in cardiovascular pathogenesis. The function of MR in angiogenesis is still controversial. This study aimed to explore the role of endothelial MR in angiogenesis and to delineate the underlying mechanism. Endothelial-hematopoietic MR knockout (EMRKO) mice were generated and subjected to hindlimb ischemia and injection of melanoma cells. Laser Doppler measurements showed that EMRKO mice had improved blood flow recovery and increased vessel density in ischemic limbs. In addition, EMRKO accelerated growth and increased the vessel density of tumors. Matrigel implantation, aortic ring assays, and tube formation assays demonstrated that MRKO endothelial cells (ECs) manifested increased angiogenic potential. MRKO ECs also displayed increased migration ability and proliferation. MRKO and MR knockdown both upregulated gene expression, protein level, and phosphorylation of signal transducer and activator of transcription 3 (STAT3). Stattic, a selective STAT3 inhibitor, attenuated the effects of MRKO on tube formation, migration, and proliferation of ECs. At the molecular level, MR interacted with CCAAT enhancer-binding protein beta (C/EBP) to suppress the transcription of STAT3. Furthermore, interactions between MR and STAT3 blocked the phosphorylation of STAT3.Finally, stattic abolished the pro-angiogenic phenotype of EMRKO mice. Taken together, endothelial MR is a negative regulator of angiogenesis, likely in a ligand-independent manner. Mechanistically, MR downregulates STAT3 that mediates the impacts of MR deficiency on the angiogenic activity of ECs and angiogenesis. Targeting endothelial MR may be a potential pro-angiogenic strategy for ischemic diseases.

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“…Importantly, MR is expressed in the heart [ 6 , 7 ], in all cell types of the vasculature, including smooth muscle cells (SMCs), endothelial cells (ECs) and fibroblasts, and has also been found in adipose tissue [ 8 ]. In this context, the MR has a relevant role in the control of cardiovascular and metabolic function [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease

et al. 2018

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The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature. Recent studies have shown that MR plays a relevant role in the control of cardiovascular and metabolic function, as well as in adipogenesis. Dysregulation of aldosterone/MR signaling represents an important cause of disease as high plasma levels of aldosterone are associated with hypertension, obesity and increased cardiovascular risk. Aldosterone displays powerful vascular effects and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Mineralocorticoid receptor activation regulates genes involved in vascular and cardiac fibrosis, calcification and inflammation. This review focuses on the role of novel potential biomarkers related to aldosterone/MR system that could help identify cardiovascular and metabolic detrimental conditions, as a result of altered MR activation. Specifically, we discuss: (1) how MR signaling regulates the number and function of different subpopulations of circulating and intra-tissue immune cells; (2) the role of aldosterone/MR system in mediating cardiometabolic diseases induced by obesity; and (3) the role of several MR downstream molecules as novel potential biomarkers of cardiometabolic diseases, end-organ damage and rehabilitation outcome.

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30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature

Cited by 80 publications

References 114 publications

Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression

Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression

Mineralocorticoid receptor negatively regulates angiogenesis through repression of STAT3 activity in endothelial cells

Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease

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