Alterations in the Balance of Cardiomyocyte Glucocorticoid and Mineralocorticoid Receptor Signaling Lead to Heart Failure

Stress is associated with adverse cardiac outcomes; however, the mechanisms underlying these effects are poorly understood. Glucocorticoids are stress hormones that regulate cell and tissue homeostasis through two closely related nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Cardiomyocytes express both these receptors but little is known concerning their coordinated actions in heart physiology and pathology. Here, we show that patients with failing hearts have a disparity in the relative levels of GR and MR compared to non-failing donor hearts. 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 cardioMRKO mice exhibited normal heart function whereas the cardioGRKO mice spontaneously developed cardiac hypertrophy and left ventricular systolic dysfunction. Surprisingly, the cardioGRMRdKO mice were protected from c...