Research ArticlePhysiology

Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice

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Science Signaling  16 Apr 2019:
Vol. 12, Issue 577, eaau9685
DOI: 10.1126/scisignal.aau9685

A balancing act for the heart

Stress increases the risk of dying from cardiometabolic disease. In humans, stress triggers the release of the hormone cortisol, which alters gene expression through activation of the glucocorticoid receptor and the structurally related mineralocorticoid receptor. Oakley et al. (see also the Focus by Chapman) generated mice with a cardiomyocyte-specific deficiency in the glucocorticoid receptor, the mineralocorticoid receptor, or both receptors. Mice that were deficient in the mineralocorticoid receptor or both receptors did not develop the heart failure seen in mice deficient in the glucocorticoid receptor. Reexpression of the mineralocorticoid receptor in the double knockout mice resulted in the development of heart failure. These results suggest that mineralocorticoid receptor antagonists are cardioprotective in patients because they promote signaling through glucocorticoid receptors.


Stress is increasingly associated with heart dysfunction and is linked to higher mortality rates in patients with cardiometabolic disease. Glucocorticoids are primary stress hormones that regulate homeostasis through two nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), both of which are present in cardiomyocytes. To examine the specific and coordinated roles that these receptors play in mediating the direct effects of stress on 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 and died prematurely from heart failure. In contrast, the cardioMRKO mice exhibited normal heart morphology and function. Despite the presence of myocardial stress, the cardioGRMRdKO mice were resistant to the cardiac remodeling, left ventricular dysfunction, and early death observed in the cardioGRKO mice. Gene expression analysis revealed the loss of gene changes associated with impaired Ca2+ handling, increased oxidative stress, and enhanced cell death and the presence of gene changes that limited the hypertrophic response and promoted cardiomyocyte survival in the double knockout hearts. Reexpression of MR in cardioGRMRdKO hearts reversed many of the cardioprotective gene changes and resulted in cardiac failure. These findings reveal a critical role for balanced cardiomyocyte GR and MR stress signaling in cardiovascular health. Therapies that shift stress signaling in the heart to favor more GR and less MR activity may provide an improved approach for treating heart disease.

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