Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure
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...
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| Format: | Article |
| Language: | English |
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Wiley
2019-08-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.118.011012 |
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| author | Diana Cruz‐Topete Robert H. Oakley Natalie G. Carroll Bo He Page H. Myers Xiaojiang Xu Megan N. Watts Krystle Trosclair Edward Glasscock Paari Dominic John A. Cidlowski |
| author_facet | Diana Cruz‐Topete Robert H. Oakley Natalie G. Carroll Bo He Page H. Myers Xiaojiang Xu Megan N. Watts Krystle Trosclair Edward Glasscock Paari Dominic John A. Cidlowski |
| author_sort | Diana Cruz‐Topete |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-13T02:13:42Z |
| format | Article |
| id | doaj.art-a13a27ea30964ec98b41bb44f98186c1 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-13T02:13:42Z |
| publishDate | 2019-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-a13a27ea30964ec98b41bb44f98186c12022-12-22T00:02:58ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802019-08-0181510.1161/JAHA.118.011012Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart FailureDiana Cruz‐Topete0Robert H. Oakley1Natalie G. Carroll2Bo He3Page H. Myers4Xiaojiang Xu5Megan N. Watts6Krystle Trosclair7Edward Glasscock8Paari Dominic9John A. Cidlowski10Department of Molecular and Cellular Physiology LSU Health Sciences Center Shreveport LASignal Transduction Laboratory National Institute of Environmental Health Sciences National Institutes of Health Department of Health and Human Services Research Triangle Park NCDepartment of Molecular and Cellular Physiology LSU Health Sciences Center Shreveport LASignal Transduction Laboratory National Institute of Environmental Health Sciences National Institutes of Health Department of Health and Human Services Research Triangle Park NCComparative Medicine Branch National Institute of Environmental Health Sciences National Institutes of Health Department of Health and Human Services Research Triangle Park NCLaboratory of Integrative Bioinformatics National Institute of Environmental Health Sciences National Institutes of Health Department of Health and Human Services Research Triangle Park NCDepartment of Cardiology LSU Health Sciences Center Shreveport LADepartment of Cellular Biology and Anatomy LSU Health Sciences Center Shreveport LADepartment of Cellular Biology and Anatomy LSU Health Sciences Center Shreveport LADepartment of Cardiology LSU Health Sciences Center Shreveport LASignal Transduction Laboratory National Institute of Environmental Health Sciences National Institutes of Health Department of Health and Human Services Research Triangle Park NCBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.118.011012cardiomyocyteglucocorticoidglucocorticoid receptorheart failuresex hormones |
| spellingShingle | Diana Cruz‐Topete Robert H. Oakley Natalie G. Carroll Bo He Page H. Myers Xiaojiang Xu Megan N. Watts Krystle Trosclair Edward Glasscock Paari Dominic John A. Cidlowski 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: Cardiovascular and Cerebrovascular Disease cardiomyocyte glucocorticoid glucocorticoid receptor heart failure sex hormones |
| title | Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure |
| title_full | Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure |
| title_fullStr | Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure |
| title_full_unstemmed | Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure |
| title_short | Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure |
| title_sort | deletion of the cardiomyocyte glucocorticoid receptor leads to sexually dimorphic changes in cardiac gene expression and progression to heart failure |
| topic | cardiomyocyte glucocorticoid glucocorticoid receptor heart failure sex hormones |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.118.011012 |
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