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Cardiomyocyte glucocorticoid receptor and transcriptional rhythms in the heart

ABSTRACT: Cardiomyocyte glucocorticoid receptor and transcriptional rhythms in the heart

PROVIDER: PRJNA991552 | ENA |

REPOSITORIES: ENA

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Cardiomyocyte glucocorticoid receptor and transcriptional rhythms in the heart

Project description:Ventricular arrhythmias demonstrate a prominent diurnal rhythm, commonly presenting in the morning on waking. Transcriptional rhythms in cardiac ion channels contribute to this phenomenon but the underlying mechanisms are incompletely understood. We have evidence in mice suggesting the glucocorticoid receptor (GR), the transcriptional effector of glucocorticoids, regulates ion channels previously implicated in the diurnal rhythm in cardiomyocyte excitability and ventricular arrhythmia susceptibility. To determine if the GR is a direct regulator of the transcriptional rhythms in the heart, RNA-seq was performed on RNA isolated from the left ventricular (LV) free wall of cardiomyocyte-specific GR knockout mice (cardioGRKO) and their littermate control mice (GRflox) at ZT0 (start of lights on) and ZT12 (start of lights off) time points.

2025-07-07 | GSE236548 | GEO

Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure

Project description:Background The contribution of glucocorticoids to sexual dimorphism in the heart is essentially unknown. Therefore, we sought to determine the sexually dimorphic actions of glucocorticoid signaling in cardiac function and gene expression. To accomplish this goal, we conducted studies on mice lacking glucocorticoid receptors (GR) in cardiomyocytes (cardioGRKO mouse model). Methods and Results Deletion of cardiomyocyte GR leads to an increase in mortality because of the development of spontaneous cardiac pathology in both male and female mice; however, females are more resistant to GR signaling inactivation in the heart. Male cardioGRKO mice had a median survival age of 6 months. In contrast, females had a median survival age of 10 months. Transthoracic echocardiography data showed phenotypic differences between male and female cardioGRKO hearts. By 3 months of age, male cardioGRKO mice exhibited left ventricular systolic dysfunction. Conversely, no significant functional deficits were observed in female cardioGRKO mice at the same time point. Functional sensitivity of male hearts to the loss of cardiomyocyte GR was reversed following gonadectomy. RNA‐Seq analysis showed that deleting GR in the male hearts leads to a more profound dysregulation in the expression of genes implicated in heart rate regulation (calcium handling). In agreement with these gene expression data, cardiomyocytes isolated from male cardioGRKO hearts displayed altered intracellular calcium responses. In contrast, female GR‐deficient cardiomyocytes presented a response comparable with controls. Conclusions These data suggest that GR regulates calcium responses in a sex‐biased manner, leading to sexually distinct responses to stress in male and female mice hearts, which may contribute to sex differences in heart disease, including the development of ventricular arrhythmias that contribute to heart failure and sudden death.

2019-12-30 | GSE120573 | GEO

Effect of cardiomyocyte-specific deletion of glucocorticoid receptor on gene expression of cultured neonatal cardiomyocytes

Project description:To investigate the role of the glucocorticoid receptor (GR) in the regulation of cardiomyocyte maturation and proliferation, we established a cardiomyocyte-specific GR knock-out (GR-cKO) mouse model by Cre-Lox technology. We thus performed gene expression profiling analysis using data obtained from RNA-seq of cardiomyocytes isolated from GR-cKO and control mouse models at neonatal stage and cultured in vitro. Our analyses unveiled a role for GR in regulating gene networks related to the energetic metabolism, which in turn may impact on cardiomyocyte proliferative and regenerative ability.

2022-05-16 | GSE202968 | GEO

Effect of cardiomyocyte-specific deletion of glucocorticoid receptor on gene expression of the cardiac tissue during early postnatal development

Project description:To investigate the role of the glucocorticoid receptor (GR) in the regulation of cardiomyocyte maturation and proliferation, we established a cardiomyocyte-specific GR knock-out (GR-cKO) mouse model by Cre-Lox technology. We thus performed gene expression profiling analysis using data obtained from RNA-seq of the cardiac tissue of GR-cKO and control mouse models extracted during the early postnatal development. Our analyses unveiled a role for GR in regulating gene networks related to the energetic metabolism, which in turn may impact on cardiomyocyte proliferative and regenerative ability.

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Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure

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Endogenous glucocorticoid rhythms regulate the circadian sensitivity to noise

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Effect of cardiomyocyte-specific deletion of glucocorticoid receptor on gene expression of cultured neonatal cardiomyocytes

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Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regualtion

Project description:Ultradian glucocorticoid rhythms are highly conserved across mammalian species, however, their functional significance is not yet fully understood. Here we demonstrate that pulsatile corticosterone replacement in adrenalectomised rats induces a dynamic pattern of glucocorticoid receptor (GR) binding at ~3,000 genomic sites in liver at the pulse peak, subsequently not found during the pulse nadir. In contrast, constant corticosterone replacement induced prolonged binding at the majority of these sites. Additionally, each pattern further induced markedly different transcriptional responses. During pulsatile treatment, intragenic occupancy by active RNA polymerase II exhibited pulsatile dynamics with transient changes in enrichment, either decreased or increased depending on the gene, which mostly returned to baseline during the inter-pulse interval. In contrast, constant corticosterone exposure induced prolonged effects on RNA polymerase II occupancy at the majority of gene targets, thus acting as a sustained regulatory signal for both transactivation and repression of glucocorticoid target genes. The nett effect of these differences were consequently seen in the liver transcriptome as RNA-seq analysis indicated that despite the same overall amount of corticosterone infused, twice the number of transcripts were regulated by constant corticosterone infusion, when compared to pulsatile. Target genes that were found to be differentially regulated in a pattern-dependent manner were enriched in functional pathways including carbohydrate, cholesterol, glucose and fat metabolism as well as inflammation, suggesting a functional role for dysregulated glucocorticoid rhythms in the development of metabolic dysfunction.

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