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Mineralocorticoid receptor (MR) trans-activation of inflammatory AP-1 signaling: dependence on DNA sequence, MR conformation, and AP-1 family member expression

ABSTRACT: Mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. The differential effects of GR and MR on inflammatory signaling and their contextual dependencies are relevant to the design of next generation drugs with improved safety and efficacy While MR has been shown to weakly repress NFκB, its role in modulating AP-1 has not been established

ORGANISM(S): Homo sapiens

PROVIDER: GSE80276 | GEO | 2016/09/20

SECONDARY ACCESSION(S): PRJNA318487

REPOSITORIES: GEO

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Cardiac aldosterone regulated genes in mice with cardiomyocytes targeted mineralocorticoid receptor overexpression (MR-Cardio mice) and their controls (Ctrl mice)

Project description:Inappropriate mineralocorticoid receptor (MR) activation is involved in cardiac diseases. The mechanisms are still unclears. Mice overexpressing MR in cardiomyocytes (MR-Cardio) and their controls (Ctrl) were treated for 7 days with aldosterone and a whole genome microarray analysis was performed.

2017-09-01 | GSE34049 | GEO

Mineralocorticoid Receptor (MR) trans-Activation of Inflammatory AP-1 Signaling: DEPENDENCE ON DNA SEQUENCE, MR CONFORMATION, AND AP-1 FAMILY MEMBER EXPRESSION.

Project description:Glucocorticoids are commonly used to treat inflammatory disorders. The glucocorticoid receptor (GR) can tether to inflammatory transcription factor complexes, such as NFκB and AP-1, and trans-repress the transcription of cytokines, chemokines, and adhesion molecules. In contrast, aldosterone and the mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. Although MR has been shown to weakly repress NFκB, its role in modulating AP-1 has not been established. Here, the effects of GR and MR on NFκB and AP-1 signaling were directly compared using a variety of ligands, two different AP-1 consensus sequences, GR and MR DNA-binding domain mutants, and siRNA knockdown or overexpression of core AP-1 family members. Both GR and MR repressed an NFκB reporter without influencing p65 or p50 binding to DNA. Likewise, neither GR nor MR affected AP-1 binding, but repression or activation of AP-1 reporters occurred in a ligand-, AP-1 consensus sequence-, and AP-1 family member-specific manner. Notably, aldosterone interactions with both GR and MR demonstrated a potential to activate AP-1. DNA-binding domain mutations that eliminated the ability of GR and MR to cis-activate a hormone response element-driven reporter variably affected the strength and polarity of these responses. Importantly, MR modulation of NFκB and AP-1 signaling was consistent with a trans-mechanism, and AP-1 effects were confirmed for specific gene targets in primary human cells. Steroid nuclear receptor trans-effects on inflammatory signaling are context-dependent and influenced by nuclear receptor conformation, DNA sequence, and the expression of heterologous binding partners. Aldosterone activation of AP-1 may contribute to its proinflammatory effects in the vasculature.

| S-EPMC5095416 | biostudies-literature

Cardiac aldosterone and corticosterone regulated genes in mice with cardiomyocytes targeted mineralocorticoid receptor overexpression (MR-Cardio mice) and their controls (Ctrl mice)

Project description:Inappropriate mineralocorticoid receptor (MR) activation is involved in cardiac diseases. MR binds aldosterone, but also glucocorticoids; the identity of the ligand responsible for the deleterious effects of cardiac MR activation is still unclear. Mice overexpressing MR in cardiomyocytes (MR-Cardio) and their controls (Ctrl) were treated for 7 days with aldosterone or corticosterone and a whole genome microarray analysis was performed.

2017-09-01 | GSE33022 | GEO

Smooth muscle cell mineralocorticoid receptor regulation of vascular microRNAs with aging

Project description:We used a smooth muscle cell-specific mineralocorticoid receptor knockout mouse to generate young and aged MR-intact and SMC-MR-KO aortic miRNA to examine the effect of age on vascular miRNA alterations in the presence and absence of SMC-MR. For more information about the mouse model see: McCurley, A et al. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med. 2012 Sep;18(9):1429-33 Total miRNA was extracted from young (3-4 mo) and aged male (12mo) MR-intact and SMC-MR-KO mice to investigate aging-induced alterations in vascular miRNA expression

2016-07-29 | E-GEOD-84960 | biostudies-arrayexpress

Molecular signature of mineralocorticoid signalling in cardiomyocytes

Project description:Gene expression analysis of hearts from double transgenic mice with conditional, cardiomyocyte-specific, overexpression of the mineralocorticoid (MR) or of the glucocorticoid receptor (GR). GR-mice vs controls, MR-mice vs controls. GR: 3 sample pools hybridized to 2 microarrays each. MR: 1 sample pool hybridized to 3 microarrays. Microarray contains triplicate spots.

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Cistrome of the Aldosterone-activated Mineralocorticoid Receptor in Human Renal Cells

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Smooth muscle cell mineralocorticoid receptor regulation of vascular mRNAs with aging

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2017-08-10 | GSE102397 | GEO

Smooth muscle cell mineralocorticoid receptor regulation of vascular microRNAs with aging

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Molecular signature of mineralocorticoid signalling in cardiomyocytes

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Cistrome of the Aldosterone-activated Mineralocorticoid Receptor in Human Renal Cells

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