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New insights into the roles of glucocorticoid signaling dysregulation in pathological cardiac hypertrophy

Abstract

Pathological cardiac hypertrophy is a process of abnormal remodeling of the myocardium in response to stress overload or ischemia that results in myocardial injury, which is an independent risk factor for the increased morbidity and mortality of heart failure. Elevated circulating glucocorticoids (GCs) levels are associated with an increased risk of pathological cardiac hypertrophy, but the exact role remains unclear. In the heart, GCs exerts physiological and pharmacological effects by binding the glucocorticoid receptor (GR, NR3C1). However, under the state of tissue damage or oxidative stress, GCs can also bind the closely related mineralocorticoid receptor (MR, NR3C2) to exert a detrimental effect on cardiac function. In addition, the bioavailability of GCs at the cellular level is mainly regulated by tissue-specific metabolic enzymes 11β-hydroxysteroid dehydrogenases (11β-HSDs), including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and type 2 (11β-HSD2), which catalyze the interconversion of active GCs. In this paper, we provide an overview of GC signaling and its physiological roles in the heart and highlight the dynamic and diverse roles of GC signaling dysregulation, mediated by excessive ligand GCs levels, GR/MR deficiency or overexpression, and local GCs metabolic disorder by 11β-HSDs, in the pathology of cardiac hypertrophy. Our findings will provide new ideas and insights for the search for appropriate intervention targets for pathological cardiac hypertrophy.

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Funding

This work was supported by the National Natural Scientific Funding of China (No.81672264 and No.81871858).

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Correspondence to Danyan Xu.

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We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work; there is no professional or other personal interest of any nature or kind in the manuscript entitled “New insights into the roles of glucocorticoid signaling dysregulation in pathological cardiac hypertrophy.”

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Yang, J., Chen, Y., Li, X. et al. New insights into the roles of glucocorticoid signaling dysregulation in pathological cardiac hypertrophy. Heart Fail Rev 27, 1431–1441 (2022). https://doi.org/10.1007/s10741-021-10158-x

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Keywords

  • Glucocorticoids (GCs)
  • Glucocorticoid receptor (GR)
  • Mineralocorticoid receptor (MR)
  • Pathological cardiac hypertrophy
  • 11β-hydroxysteroid dehydrogenases (11β-HSDs)