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

Robert H. Oakley, Diana Cruz-Topete, Bo He, Julie F. Foley, Page H. Myers, Xiaojiang Xu, Celso E. Gomez-Sanchez, Pierre Chambon, Monte Willis, John A. Cidlowski

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 Ca 2+ 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.

Original languageEnglish (US)
Article numbereaau9685
JournalScience Signaling
Volume12
Issue number577
DOIs
StatePublished - Apr 16 2019

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Mineralocorticoid Receptors
Glucocorticoid Receptors
Cardiac Myocytes
Heart Diseases
Left Ventricular Dysfunction
Genes
Heart Failure
Cardiomegaly
Cytoplasmic and Nuclear Receptors
Glucocorticoids
Oxidative stress
Oxidative Stress
Homeostasis
Cell Death
Cell death
Gene expression
Hormones
Gene Expression
Mortality
Health

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Oakley, R. H., Cruz-Topete, D., He, B., Foley, J. F., Myers, P. H., Xu, X., ... Cidlowski, J. A. (2019). Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice. Science Signaling, 12(577), [eaau9685]. https://doi.org/10.1126/scisignal.aau9685

Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice. / Oakley, Robert H.; Cruz-Topete, Diana; He, Bo; Foley, Julie F.; Myers, Page H.; Xu, Xiaojiang; Gomez-Sanchez, Celso E.; Chambon, Pierre; Willis, Monte; Cidlowski, John A.

In: Science Signaling, Vol. 12, No. 577, eaau9685, 16.04.2019.

Research output: Contribution to journalArticle

Oakley, RH, Cruz-Topete, D, He, B, Foley, JF, Myers, PH, Xu, X, Gomez-Sanchez, CE, Chambon, P, Willis, M & Cidlowski, JA 2019, 'Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice', Science Signaling, vol. 12, no. 577, eaau9685. https://doi.org/10.1126/scisignal.aau9685
Oakley, Robert H. ; Cruz-Topete, Diana ; He, Bo ; Foley, Julie F. ; Myers, Page H. ; Xu, Xiaojiang ; Gomez-Sanchez, Celso E. ; Chambon, Pierre ; Willis, Monte ; Cidlowski, John A. / Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice. In: Science Signaling. 2019 ; Vol. 12, No. 577.
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