Global Gene Changes in Hearts from CardioMRKO Mice

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 that regulate homeostasis through two closely related nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Cardiomyocytes express both receptors but little is known concerning their 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 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 cardiac disease. Genome-wide microarrays were performed on isolated hearts from each mouse model to 1) identify genes subject to regulation by GR alone, MR alone, or both GR and MR and 2) identify the genes responsible for the cardiac pathology in the cardioGRKO mice and for the cardioprotection in the cardioGRMRdKO mice. Mice harboring a floxed MR allele (MRflox) were crossed with cardiomyocyte-specific αMHC-Cre mice to generate the cardioMRKO mice. Total RNA for microarray analysis was harvested from whole hearts isolated from 4 male 1-month old cardioMRKO mice, 4 male 1-month old littermate controls, 4 male 2-month old cardioMRKO mice, and 4 male 2-month old littermate controls. Littermate controls were Cre negative MRflox mice.