Abstract 13196: Essential Role for Cardiomyocyte Glucocorticoid Receptors for the Prevention of Heart Disease
Glucocorticoids are primary stress hormones essential for life that have been implicated in cardiovascular health and disease. Whether these cardiovascular effects reflect systemic actions of glucocorticoids and/or direct actions of these hormones on cardiomyocytes 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) on both pure (C57BL/6) and mixed (FVB/C57BL/6) backgrounds. The cardioGRKO mice are born at the expected Mendelian ratio but die prematurely from spontaneous cardiovascular disease. By three months of age, mice deficient in cardiomyocyte GR display a significant 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. Global gene expression analysis of cardioGRKO hearts prior to pathology onset revealed aberrant regulation of a large cohort of genes associated with cardiovascular disease. 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 GR signaling leads to spontaneous cardiac hypertrophy, heart failure, and death, revealing for the first time an obligate role for glucocorticoids in maintaining normal cardiovascular function. Moreover, our data suggest that pharmacological modulation of GR signaling in cardiomyocytes may provide a promising new approach for treating heart disease.
- © 2013 by American Heart Association, Inc.