ESPE2018 Symposia Molecular Mechanisms of Tissue Sensitivity to Glucocorticoids: Potential Clinical Implications (3 abstracts)
Cardiomyocyte Glucocorticoid and Mineralocorticoid Receptors Antagonistically Regulate Heart Disease
Robert H Oakley , Diana Cruz-Topete , Bo He , Julie F Foley , Page H Myers , Monte S Willis , Celso E Gomez-Sanchez , Pierre Chambo & John A Cidlowski
NIEHS/NIH, Research Triangle Park, Durham, North Carolina, USA
Stress is increasingly associated with cardiac disease. Glucocorticoids are primary stress hormones that regulate homeostasis through two nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Cardiomyocytes express both receptors but little is known concerning their specific and coordinated actions in heart physiology and pathology. To examine the in vivo function of glucocorticoid signaling in the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO), MR (cardioMRKO), or both GR and MR (cardioGRMRdKO). The cardioGRKO mice spontaneously developed cardiac hypertrophy and left ventricular systolic dysfunction whereas the cardioMRKO mice exhibited normal heart function. Surprisingly, the cardioGRMRdKO mice were protected from cardiac disease. Gene expression profiling identified cardioprotective gene changes in the double knockout hearts that limit cardiac hypertrophy and promote cardiomyocyte survival. Re-installation of MR into the cardioGRMRdKO hearts reversed the cardioprotective gene changes and resulted in cardiac dysfunction. These findings demonstrate a deleterious role for cardiac MR signaling when unopposed by GR. Moreover, they reveal the target genes and cellular responses altered by MR that contribute to cardiac pathology. Therapies that shift the balance of cardiomyocyte glucocorticoid signaling to favor more GR and less MR activity may provide an improved approach for treating heart disease.
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