Abstract 216: Genetic Deletion of Cardiomyocyte Mineralocorticoid Receptors Prevents Cardiac Dysfunction and Premature Death in Mice Lacking Glucocorticoid Receptors in the Heart

Heart failure is one of the leading causes of death in the Western world, and stress is increasingly associated with adverse cardiac outcomes. Glucocorticoids are primary stress hormones, but their direct role in heart physiology and pathology is poorly understood. The actions of glucocorticoids are mediated classically by the glucocorticoid receptor (GR); however, in cardiomyocytes glucocorticoid occupancy and activation of the mineralocorticoid receptor (MR) may also contribute to the observed glucocorticoid response. To elucidate the in vivo function of glucocorticoid signaling in the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO). The cardioGRKO mice spontaneously develop cardiac hypertrophy by 2 months of age and left ventricular systolic dysfunction and dilatation between 3-6 months of age, and they die prematurely from heart failure. The mean survival age of the cardioGRKO mice was 9.3 months, and 97% (38 of 39) of the mice died prior to reaching 12 months of age. Loss of GR in the heart was not accompanied by an increase in fibrosis. To investigate whether cardiomyocyte MR signaling contributes to the pathology in the cardioGRKO mice, we generated for the first time mice lacking both GR and MR in the heart (cardioGRMRKO). Despite showing increased expression of classic hypertrophic marker genes, the cardioGRMRKO mice were protected from the development of cardiac hypertrophy, and no major alterations were observed in the function and chamber size of the left ventricle. Moreover, the cardioGRMRKO mice were protected from premature death as 94% (15 of 16) of the mice survived past the 13 month study endpoint. Microarray analysis revealed marked differences in gene expression profiles between the cardioGRKO and cardioGRMRKO hearts. These findings reveal that cardiomyocyte MR signaling, when unopposed by GR signaling, plays a major role in the progression of cardiac disease. Moreover, they suggest that combining GR agonists with MR antagonists may represent an improved therapeutic approach for treating heart failure.