Abstract 13093: An Imbalance in Cardiomyocyte Glucocorticoid and Mineralocorticoid Receptor Signaling Leads to Heart Failure

Abstract

Stress is increasingly associated with adverse cardiac outcomes; however the mechanisms underlying these effects are poorly understood. Glucocorticoids are primary 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 whether an imbalance in their signaling contributes to cardiac disease. 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 the cardiac disease observed for the cardioGRKO mice. At a molecular level, pathological gene changes present in the GR deficient hearts were also found in the double knockout hearts whereas specific cardioprotective gene changes were detected only in hearts from the cardioGRMRdKO mice. Re-installation of MR into the cardioGRMRdKO hearts by adeno-associated virus gene delivery reversed these cardioprotective gene changes and resulted in cardiac dysfunction. These findings reveal critical gene-regulatory roles for both GR and MR in the heart and suggest that an imbalance in these two signaling pathways leads to heart disease. Therapies designed to modulate cardiomyocyte glucocorticoid signaling to favor more GR and less MR activity may provide new approaches for treating the failing heart.