Gene expression data from corticosteroid-treated neonatal rat cardiomyocytes
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE12752 | GEO | 2009/05/01
SECONDARY ACCESSION(S): PRJNA111005
REPOSITORIES: GEO
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Project description:Recent studies have highlighted the role of adrenal corticosteroid signaling in cardiac physiology and pathophysiology. It is known that glucocorticoids and aldosterone are able to bind glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and these ligand-receptor interactions are redundant. Therefore, it has been impossible to delineate how these nuclear receptors couple with corticosteroid ligands and differentially regulate gene expression for operation of their distinct functions in the heart. Here, to particularly define the role of GR, we applied ligand-based approach involving GR-specific agonist cortivazol (CVZ) and GR antagonist RU486, and performed microarray analysis using rat neonatal cardiomyocytes. We indicated that glucocorticoids appear to be a major determinant of GR-mediated gene expression when compared with aldosterone. Moreover, expression profiles of these genes highlighted numerous roles of glucocorticoids in various aspects of cardiac physiology. Experiment Overall Design: We analyzed gene expression changes after exposure of cells to corticosterone (COR), aldosterone (ALD), and cortivazol (CVZ) in the absence or presence of GR antagonist RU486. Since our preliminary experiments using several cell lines showed that expression of many GR target genes was induced by glucocorticoids in 3 h and to avoid secondary effects of the products of GR-regulated genes, we in the present study set the time periods of exposure to these ligands as 3 h. DNA microarray experiments were performed twice with the same protocol except for RU486 treatment.
2009-05-11 | E-GEOD-12752 | biostudies-arrayexpress
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
Project description:The late-gestation fetal lung has relatively high levels of expression of the mineralocorticoid receptor (MR) as well as the glucocorticoid receptor (GR), suggesting that endogenous corticosteroids may act in the lung through binding at MR as well as GR. This study was designed to determine the effects of physiologically relevant increases in steroids on MR and GR in the late-gestation lung. The GR agonist, betamethasone, the MR agonist, aldosterone, or both agonists were infused intravenously for 48 hours in ovine fetuses of approximately 130 days gestation. Effects on airway pressures during stepwise inflation of the in situ lung, expression of ENaC and Na,K ATPase, and elastin and collagen content were determined at the end of the infusions. We found that aldosterone significantly reduced the initial airway pressures measured in situ during inflation. This effect did not occur with betamethasone alone or in combination with aldosterone. Conversely, betamethasone, but not aldosterone, significantly increased expression of the epithelial sodium channel (ENaC) subunit mRNAs, and collagen and elastin content in the lungs. Aldosterone altered novel gene pathways in the fetal lung, suggesting effects on lung compliance via genes which influence immune pathways and lung stiffness. The results are consistent with corticosteroid-induced fluid reabsorption at birth through GR rather than MR, but suggest that MR contributes effects facilitating lung inflation with the first breaths via nonclassical mechanisms. 4 sets of twin sheep fetuses at approximately 130d gestation (term is 147d) were used. One twin was infused with 0.2 mg aldosterone for 48 h, the other received vehicle.
2014-08-07 | E-GEOD-53048 | biostudies-arrayexpress
Project description:The late-gestation fetal lung has relatively high levels of expression of the mineralocorticoid receptor (MR) as well as the glucocorticoid receptor (GR), suggesting that endogenous corticosteroids may act in the lung through binding at MR as well as GR. This study was designed to determine the effects of physiologically relevant increases in steroids on MR and GR in the late-gestation lung. The GR agonist, betamethasone, the MR agonist, aldosterone, or both agonists were infused intravenously for 48 hours in ovine fetuses of approximately 130 days gestation. Effects on airway pressures during stepwise inflation of the in situ lung, expression of ENaC and Na,K ATPase, and elastin and collagen content were determined at the end of the infusions. We found that aldosterone significantly reduced the initial airway pressures measured in situ during inflation. This effect did not occur with betamethasone alone or in combination with aldosterone. Conversely, betamethasone, but not aldosterone, significantly increased expression of the epithelial sodium channel (ENaC) subunit mRNAs, and collagen and elastin content in the lungs. Aldosterone altered novel gene pathways in the fetal lung, suggesting effects on lung compliance via genes which influence immune pathways and lung stiffness. The results are consistent with corticosteroid-induced fluid reabsorption at birth through GR rather than MR, but suggest that MR contributes effects facilitating lung inflation with the first breaths via nonclassical mechanisms.
2014-08-07 | GSE53048 | GEO
Project description:Heart failure is one of the leading causes of death in the Western world, and stress is increasingly associated with adverse cardiac outcomes. Glucocorticoids are primary stress hormones that regulate homeostasis through two closely related nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Cardiomyocytes express both receptors but little is known concerning their coordinated actions in heart physiology and pathology. To examine the in vivo function of glucocorticoid signaling in the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO), MR (cardioMRKO), or both GR and MR (cardioGRMRdKO). The cardioMRKO mice exhibited normal heart function whereas the cardioGRKO mice spontaneously developed cardiac hypertrophy and left ventricular systolic dysfunction. Surprisingly, the cardioGRMRdKO mice were protected from cardiac disease. Genome-wide microarrays were performed on isolated hearts from each mouse model to 1) identify genes subject to regulation by GR alone, MR alone, or both GR and MR and 2) identify the genes responsible for the cardiac pathology in the cardioGRKO mice and for the cardioprotection in the cardioGRMRdKO mice.
2019-04-17 | GSE95727 | GEO
Project description:Heart failure is one of the leading causes of death in the Western world, and stress is increasingly associated with adverse cardiac outcomes. Glucocorticoids are primary stress hormones that regulate homeostasis through two closely related nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Cardiomyocytes express both receptors but little is known concerning their coordinated actions in heart physiology and pathology. To examine the in vivo function of glucocorticoid signaling in the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO), MR (cardioMRKO), or both GR and MR (cardioGRMRdKO). The cardioMRKO mice exhibited normal heart function whereas the cardioGRKO mice spontaneously developed cardiac hypertrophy and left ventricular systolic dysfunction. Surprisingly, the cardioGRMRdKO mice were protected from cardiac disease. Genome-wide microarrays were performed on isolated hearts from each mouse model to 1) identify genes subject to regulation by GR alone, MR alone, or both GR and MR and 2) identify the genes responsible for the cardiac pathology in the cardioGRKO mice and for the cardioprotection in the cardioGRMRdKO mice.
2019-04-17 | GSE95719 | GEO
Project description:Heart failure is one of the leading causes of death in the Western world, and stress is increasingly associated with adverse cardiac outcomes. Glucocorticoids are primary stress hormones that regulate homeostasis through two closely related nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Cardiomyocytes express both receptors but little is known concerning their coordinated actions in heart physiology and pathology. To examine the in vivo function of glucocorticoid signaling in the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO), MR (cardioMRKO), or both GR and MR (cardioGRMRdKO). The cardioMRKO mice exhibited normal heart function whereas the cardioGRKO mice spontaneously developed cardiac hypertrophy and left ventricular systolic dysfunction. Surprisingly, the cardioGRMRdKO mice were protected from cardiac disease. Genome-wide microarrays were performed on isolated hearts from each mouse model to 1) identify genes subject to regulation by GR alone, MR alone, or both GR and MR and 2) identify the genes responsible for the cardiac pathology in the cardioGRKO mice and for the cardioprotection in the cardioGRMRdKO mice.
2019-04-17 | GSE95732 | GEO
Project description:Glucocorticoids are widely used to treat inflammatory disorders. Prolonged use results in side effects including osteoporosis, diabetes and obesity. The selective glucocorticoid receptor (GR) modulator Compound A (CpdA) exhibits an inflammation-suppressive effect, largely in absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated using an unbiased proteomics approach. We found that the autophagy receptor p62 but not GR mediates the anti-inflammatory action of CpdA in macrophages. CpdA drives the upregulation of p62 by recruiting the NRF2 transcription factor to its promoter. Contrarily, the classic GR ligand dexamethasone recruits GR to p62 and other NRF2 controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA are able to induce autophagy, albeit in a cell-type and time-dependent manner. Suppression of LPS-induced IL-6 and MCP1 genes in bone marrow-derived macrophages by CpdA is hampered upon p62 silencing, confirming that p62 is essential for the anti-inflammatory capacity of CpdA. Together, these results demonstrate how off-target mechanisms of selective GR ligands may establish a more efficient anti-inflammatory therapy
2022-06-03 | PXD007793 | Pride
Project description:Glucocorticoids are steroid hormones that are essential for life in mammals. Therapeutically, they are some of the most cost-effective drugs for the treatment of inflammatory diseases ranging from skin rashes to COVID-19, but their use is limited by adverse effects. Glucocorticoids exert their effects via the glucocorticoid receptor, a type I nuclear hormone receptor which modulates gene expression. The transcriptional activity of some related, but nuclear restricted, type II nuclear hormone receptors can be enhanced by a family of intracellular transport proteins, the fatty acid binding proteins (FABPs). We find that the transcriptional activity of the GR can be altered by a sub-set of FABP family members dependent on the GR-ligand. The ability of some FABPs to selectively promote or limit the transcriptional activity of the GR in a ligand-dependent manner could facilitate the discovery of drugs that narrow GR activity to only the desired subset of therapeutically relevant genes.
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Project description:Estrogen receptor (ER) positive breast cancers exist in a complex environment of steroid hormones and their cognate receptors. Receptors for estrogens, progestogens (PR), androgens (AR), glucocorticoids (GR) and mineralocorticoids (MR) are variably expressed in these hormone- sensitive breast cancers. Clinical translation of crosstalk among these receptors has been limited by an incomplete understanding of ER reprogramming by PR, GR, AR and MR (NR3C receptors). This study reports that each of the NR3C receptors reprograms ER chromatin binding to sites enriched for NR3C binding motifs and that hormonal co-treatment increases the likelihood of ER binding to estrogen response elements. A major overlap is observed among ER conserved sites, but not among ER sites that are lost or gained due to reprogramming by each of the NR3C receptors. This stability of ER genomic binding is reflected in the resulting transcriptomes, as there is significant overlap among genes whose expression is unaltered in response to joint hormonal interventions but not among genes whose expression is enhanced or opposed by an individual NR3C receptor. The addition of NR3C ligands can enhance or oppose estrogen-mediated induction and repression of gene transcription, resulting in net agonism or antagonism of ER-mediated actions at gene loci and of cellular pathways of interest. In addition to differential modulation of chromatin binding, differences in cofactor associations for ER, PR and GR likely contribute to the divergent functions of these receptors in breast cancer. Among the NR3C receptors, MR activation differentially reprograms ER chromatin binding and, in contrast to ligands for PR, GR or AR, the MR ligand aldosterone does not inhibit estrogen-induced cell proliferation or potentiate the anti-proliferative effect of tamoxifen in ER+ MCF7 cells. PR, GR, AR and MR may be functionally relevant in ER+ breast cancer because higher expression of these NR3C receptors; or genes whose estrogen-regulated expression is altered by each of these receptors is significantly associated with better overall and relapse-free survival. In summary, this study highlights the diverse yet overlapping activities of NR3C receptors in reprogramming ER signaling.
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