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| Status |
Public on Dec 30, 2019 |
| Title |
Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Examination of transcriptome under two different conditions (Normal GR levels in cardiomyocytes vs. no GR expression in cardiomyocytes)
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| Contributor(s) |
Cruz-Topete D, Oakley R, Burford N, Myers P, Xu X, Cidlowski J |
| Citation(s) |
31311395 |
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| Submission date |
Sep 27, 2018 |
| Last update date |
Mar 30, 2020 |
| Contact name |
Xiaojiang Xu |
| Phone |
984-287-3622
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| Organization name |
NIEHS
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| Lab |
ESCBL
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| Street address |
111 T. W. Alexander Dr.,
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| City |
RTP |
| State/province |
North Carolina |
| ZIP/Postal code |
27709 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (12)
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| GSM3403530 |
male Homozygous GR floxed (GRloxP,loxP) 1 |
| GSM3403531 |
male Homozygous GR floxed (GRloxP,loxP) 2 |
| GSM3403532 |
male Homozygous GR floxed (GRloxP,loxP) 3 |
| GSM3403533 |
male GRloxP/loxPαMHCCre/+ mice (designated cardioGRKO) 1 |
| GSM3403534 |
male GRloxP/loxPαMHCCre/+ mice (designated cardioGRKO) 2 |
| GSM3403535 |
male GRloxP/loxPαMHCCre/+ mice (designated cardioGRKO) 3 |
| GSM3403536 |
female Homozygous GR floxed (GRloxP,loxP) 1 |
| GSM3403537 |
female Homozygous GR floxed (GRloxP,loxP) 2 |
| GSM3403538 |
female Homozygous GR floxed (GRloxP,loxP) 3 |
| GSM3403539 |
female GRloxP/loxPαMHCCre/+ mice (designated cardioGRKO) 1 |
| GSM3403540 |
female GRloxP/loxPαMHCCre/+ mice (designated cardioGRKO) 2 |
| GSM3403541 |
female GRloxP/loxPαMHCCre/+ mice (designated cardioGRKO) 3 |
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| Relations |
| BioProject |
PRJNA493624 |
| SRA |
SRP162795 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE120573_Heart_GRKO_htseq_count_DESeq_exp_log2_normalized.txt.gz |
1.4 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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