Cardiomyocyte glucocorticoid receptor and transcriptional rhythms in the heart
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PROVIDER: PRJNA991552 | ENA |
REPOSITORIES: ENA
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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
Project description:Caloric restriction extends lifespan and healthspan across species, with feeding times synchronized to circadian rhythms further maximizing its benefits. However, the mechanisms linking diet, diurnal rhythms, and lifespan are not fully understood. In mice, the time point most strongly tied to dietary effects on lifespan coincides with the peak of glucocorticoid secretion (ZT12, lights-off). Caloric restriction raises circulating glucocorticoid hormone levels, but their functional relevance remains untested. We show that the glucocorticoid receptor (GR) is critical for the effects of caloric restriction. Hepatocyte-specific GR mutant mice fail to respond to caloric restriction indicating that increased glucocorticoid amplitudes support its benefits. Using multiomics techniques in murine liver, we find that nutrient deprivation elicits a nuclear switch from active STAT signaling to increased FOXO1 activity, enabling the GR to activate a unique diet-specific gene expression program. Taken together, our results suggest that glucocorticoid rhythms are crucial for caloric restriction-induced metabolic reprogramming.
2025-11-04 | GSE298149 | GEO
Project description:Caloric restriction extends lifespan and healthspan across species, with feeding times synchronized to circadian rhythms further maximizing its benefits. However, the mechanisms linking diet, diurnal rhythms, and lifespan are not fully understood. In mice, the time point most strongly tied to dietary effects on lifespan coincides with the peak of glucocorticoid secretion (ZT12, lights-off). Caloric restriction raises circulating glucocorticoid hormone levels, but their functional relevance remains untested. We show that the glucocorticoid receptor (GR) is critical for the effects of caloric restriction. Hepatocyte-specific GR mutant mice fail to respond to caloric restriction indicating that increased glucocorticoid amplitudes support its benefits. Using multiomics techniques in murine liver, we find that nutrient deprivation elicits a nuclear switch from active STAT signaling to increased FOXO1 activity, enabling the GR to activate a unique diet-specific gene expression program. Taken together, our results suggest that glucocorticoid rhythms are crucial for caloric restriction-induced metabolic reprogramming.
2025-11-04 | GSE248866 | GEO
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
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
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.
2022-05-16 | GSE202969 | GEO
Project description:Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure
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Project description:Endogenous glucocorticoid rhythms regulate the circadian sensitivity to noise
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Project description:Promoting the proliferation of endogenous cardiomyocytes represents a promising strategy for treating cardiac injuries. Identifying key factors that regulate cardiomyocyte proliferation can advance the development of novel therapies for heart regeneration. Here we identify that FOXK1 and FOXK2 act as master regulators of cardiomyocyte proliferation and metabolism. The expression of FOXK1 and FOXK2 decreased with postnatal heart development. Cardiomyocyte-specific knockout of Foxk1 or Foxk2 inhibited neonatal heart regeneration after myocardial infarction (MI) injury. Conversely, AAV9-mediated cardiomyocyte-specific overexpression of FOXK1 or FOXK2 prolonged the postnatal proliferative window of cardiomyocytes and enhanced cardiac repair in adult mice by promoting endogenous cardiomyocyte proliferation after MI. Mechanistically, FOXK1 and FOXK2 induce Ccnb1 and Cdk1 transcription and cardiomyocyte cell cycle progression, respectively. Ccnb1 knockdown hindered FOXK1 overexpression-induced cardiomyocyte proliferation, and the same effect was observed when Cdk1 was knocked down in FOXK2 overexpressing cardiomyocytes. Additionally, we further revealed that FOXK1 and FOXK2 induced a metabolic shift toward glycolysis by promoting HIF1α expression in cardiomyocytes, which favors cardiomyocyte proliferation. Our findings identify FOXK1 and FOXK2 as critical triggers of cardiomyocyte proliferation and define these two transcription factors as novel therapeutic targets for myocardial infarction.
2025-02-13 | MTBLS12191 | MetaboLights
Project description:Effect of cardiomyocyte-specific deletion of glucocorticoid receptor on gene expression of cultured neonatal cardiomyocytes
| PRJNA837897 | ENA