Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

Robert H. Oakley, Rongqin Ren, Diana Cruz-Topete, Gary S. Bird, Page H. Myers, Michael C. Boyle, Michael D. Schneider, Monte S. Willis, John A. Cidlowski

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Heart failure is a leading cause of death in humans, and stress is increasingly associated with adverse cardiac outcomes. Glucocorticoids are primary stress hormones, but their direct role in cardiovascular health and disease is poorly understood. To determine the in vivo function of glucocorticoid signaling in the heart, we generated mice with cardiomyocyte-specific deletion of the glucocorticoid receptor (GR). These mice are born at the expected Mendelian ratio, but die prematurely from spontaneous cardiovascular disease. By 3 mo of age, mice deficient in cardiomyocyte GR display a marked reduction in left ventricular systolic function, as evidenced by decreases in ejection fraction and fractional shortening. Heart weight and left ventricular mass are elevated, and histology revealed cardiac hypertrophy without fibrosis. Removal of endogenous glucocorticoids and mineralocorticoids neither augmented nor lessened the hypertrophic response. Global gene expression analysis of knockout hearts before pathology onset revealed aberrant regulation of a large cohort of genes associated with cardiovascular disease as well as unique disease genes associated with inflammatory processes. Genes important for maintaining cardiac contractility, repressing cardiac hypertrophy, promoting cardiomyocyte survival, and inhibiting inflammation had decreased expression in the GR-deficient hearts. These findings demonstrate that a deficiency in cardiomyocyte glucocorticoid signaling leads to spontaneous cardiac hypertrophy, heart failure, and death, revealing an obligate role for GR in maintaining normal cardiovascular function. Moreover, our findings suggest that selective activation of cardiomyocyte GR may represent an approach for the prevention of heart disease.

Original languageEnglish (US)
Pages (from-to)17035-17040
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number42
DOIs
StatePublished - Oct 15 2013
Externally publishedYes

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    Oakley, R. H., Ren, R., Cruz-Topete, D., Bird, G. S., Myers, P. H., Boyle, M. C., Schneider, M. D., Willis, M. S., & Cidlowski, J. A. (2013). Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease. Proceedings of the National Academy of Sciences of the United States of America, 110(42), 17035-17040. https://doi.org/10.1073/pnas.1302546110