Cardiac GR and MR: From Development to Pathology

Richardson, Rachel; Batchen, Emma; Denvir, Martin A.; Gray, Gillian A.; Chapman, Karen

doi:10.1016/j.tem.2015.10.001

Cited by 32 publications

(33 citation statements)

References 66 publications

(75 reference statements)

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“…Recent studies have shown that 11β-HSD1 is expressed in myocardial cells, including notably cardiac fibroblasts. Global 11β-HSD1 deficiency has effects on cardiac growth and physiological function that are more subtle than those associated with GR deletion (Oakley & Cidlowski 2015, Richardson et al 2016), or adrenalectomy (Cruz-Topete et al 2016), but nevertheless of physiological relevance. Importantly, genetic or pharmacological depletion of 11β-HSD1 also prevents adverse cardiac remodelling and the development of heart failure after MI (McSweeney et al 2010, Gordon et al 2014, White et al 2016).…”

Section: Resultsmentioning

confidence: 99%

“…2A). Cardiomyocyte GR activation in the neonatal period promotes the switch from proliferative to hypertrophic growth (Richardson et al 2016). MR activation in the same period promotes proliferation (Feng et al 2013).…”

Section: β-Hsd1 In Postnatal Growth Of the Myocardiummentioning

confidence: 99%

“…Preclinical studies have revealed the potential benefits of blocking GR in cardiovascular disease (Small et al 2005, Oakley & Cidlowski 2015, Richardson et al 2016), but essential physiological roles of GR activation preclude the use of GR antagonists in vivo . With their distinct profile of action, 11β-HSD1 inhibitors offer an alternative means of regulating GR and MR activation in specific cells.…”

Section: Therapeutic Potential Of 11β-hsd1 Inhibition In Myocardial Dmentioning

confidence: 99%

“…In the heart, activation of both GR and MR has an impact on cardiac development, physiology and pathophysiology (reviewed in Oakley & Cidlowski 2015 and Richardson et al 2016). GR and MR are highly related and belong to the nuclear receptor family of transcriptional regulators (Biddie et al 2010), although some corticosteroid actions may be mediated by non-classical signalling through cell-surface receptors (Mihailidou & Funder 2005, Samarasinghe et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

Gray

White

Castellan

et al. 2017

Journal of Molecular Endocrinology

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Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and mineralocorticoid (MR) receptors. Systemic corticosteroid concentration depends largely on the activity of the hypothalamic–pituitary–adrenal (HPA) axis, but glucocorticoid can also be regenerated from intrinsically inert metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), selectively increasing glucocorticoid levels within cells and tissues. Extensive studies have revealed the roles for glucocorticoid regeneration by 11β-HSD1 in liver, adipose, brain and other tissues, but until recently, there has been little focus on the heart. This article reviews the evidence for glucocorticoid metabolism by 11β-HSD1 in the heart and for a role of 11β-HSD1 activity in determining the myocardial growth and physiological function. We also consider the potential of 11β-HSD1 as a therapeutic target to enhance repair after myocardial infarction and to prevent the development of cardiac remodelling and heart failure.

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Section: Resultsmentioning

confidence: 99%

Section: β-Hsd1 In Postnatal Growth Of the Myocardiummentioning

confidence: 99%

Section: Therapeutic Potential Of 11β-hsd1 Inhibition In Myocardial Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

Gray

White

Castellan

et al. 2017

Journal of Molecular Endocrinology

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“…In the absence of 11β-HSD2, endogenous glucocorticoids can bind to the mineralocorticoid receptor (MR) as well as the glucocorticoid receptor (GR) [37]. Both MR and GR belong to the same nuclear hormone receptor superfamily, and share high sequence identity.…”

Section: Introductionmentioning

confidence: 99%

A novel role for the mineralocorticoid receptor in glucocorticoid driven vascular calcification

Zhu

Rashdan

Chapman

et al. 2016

Vascular Pharmacology

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Vascular calcification, which is common in the elderly and in patients with atherosclerosis, diabetes and chronic renal disease, increases the risk of cardiovascular morbidity and mortality. It is a complex, active and highly regulated cellular process that resembles physiological bone formation. It has previously been established that pharmacological doses of glucocorticoids facilitate arterial calcification. However, the consequences for vascular calcification of endogenous glucocorticoid elevation have yet to be established. Glucocorticoids (cortisol, corticosterone) are released from the adrenal gland, but can also be generated within cells from 11-keto metabolites of glucocorticoids (cortisone, 11-dehydrocorticosterone [11-DHC]) by the enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In the current study we hypothesized that endogenous glucocorticoids facilitate vascular smooth muscle cell (VSMC) calcification and investigated the receptor-mediated mechanism underpinning this process.In vitro studies revealed increased phosphate-induced calcification in mouse VSMCs following treatment for 7 days with corticosterone (100 nM; 7.98 fold; P < 0.01), 11-DHC (100 nM; 7.14 fold; P < 0.05) and dexamethasone (10 nM; 7.16 fold; P < 0.05), a synthetic glucocorticoid used as a positive control. Inhibition of 11β-HSD isoenzymes by 10 μM carbenoxolone reduced the calcification induced by 11-DHC (0.37 fold compared to treatment with 11-DHC alone; P < 0.05). The glucocorticoid receptor (GR) antagonist mifepristone (10 μM) had no effect on VSMC calcification in response to corticosterone or 11-DHC. In contrast, the mineralocorticoid receptor (MR) antagonist eplerenone (10 μM) significantly decreased corticosterone- (0.81 fold compared to treatment with corticosterone alone; P < 0.01) and 11-DHC-driven (0.64 fold compared to treatment with 11-DHC alone; P < 0.01) VSMC calcification, suggesting this glucocorticoid effect is MR-driven and not GR-driven. Neither corticosterone nor 11-DHC altered the mRNA levels of the osteogenic markers PiT-1, Osx and Bmp2. However, DAPI staining of pyknotic nuclei and flow cytometry analysis of surface Annexin V expression showed that corticosterone induced apoptosis in VSMCs.This study suggests that in mouse VSMCs, corticosterone acts through the MR to induce pro-calcification effects, and identifies 11β-HSD-inhibition as a novel potential treatment for vascular calcification.

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