Open AccessDeletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure
Author(s) -
CruzTopete Diana,
Oakley Robert H.,
Carroll Natalie G.,
He Bo,
Myers Page H.,
Xu Xiaojiang,
Watts Megan N.,
Trosclair Krystle,
Glasscock Edward,
Dominic Paari,
Cidlowski John A.
Publication year - 2019
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.118.011012
Subject(s) - medicine , sexual dimorphism , heart failure , endocrinology , glucocorticoid receptor , glucocorticoid , phenotype , gene expression , gene , biology , genetics
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 (cardio GRKO 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 cardio GRKO 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 cardio GRKO hearts. By 3 months of age, male cardio GRKO mice exhibited left ventricular systolic dysfunction. Conversely, no significant functional deficits were observed in female cardio GRKO 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 cardio GRKO 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.