Journal article
Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure
Journal of the American Heart Association, Vol.8(15), pp.e011012-e011012
07/17/2019
DOI: 10.1161/JAHA.118.011012
PMCID: PMC6761632
PMID: 31311395
Abstract
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.
Details
- Title: Subtitle
- Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure
- Creators
- Diana Cruz-Topete - Department of Molecular and Cellular Physiology LSU Health Sciences Center Shreveport LARobert H. Oakley - National Institute of Environmental Health SciencesNatalie G. Carroll - LSU Health Sciences CenterBo He - National Institute of Environmental Health SciencesPage H. Myers - National Institute of Environmental Health SciencesXiaojiang Xu - National Institute of Environmental Health SciencesMegan N. Watts - Department of Cardiology LSU Health Sciences Center Shreveport LA.Krystle Trosclair - Department of Cellular Biology and Anatomy LSU Health Sciences Center Shreveport LAEdward Glasscock - Department of Cellular Biology and Anatomy LSU Health Sciences Center Shreveport LAPaari Dominic - Department of Cardiology LSU Health Sciences Center Shreveport LAJohn A. Cidlowski - National Institute of Environmental Health Sciences
- Resource Type
- Journal article
- Publication Details
- Journal of the American Heart Association, Vol.8(15), pp.e011012-e011012
- Publisher
- John Wiley and Sons Inc
- DOI
- 10.1161/JAHA.118.011012
- PMID
- 31311395
- PMCID
- PMC6761632
- ISSN
- 2047-9980
- eISSN
- 2047-9980
- Grant note
- Louisiana State University Health Sciences Center‐Shreveport National Institute of Environmental Health Sciences R01 NS‐100954; R01 NS‐099188 / National Institutes of Health
- Alternative title
- Cruz‐Topete et al
- Language
- English
- Date published
- 07/17/2019
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984366263902771
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