Hierarchical and context-dependent GR-MR signalling governs endogenous corticosteroid decoding in the heart
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
ABSTRACT Endogenous corticosteroids bind both the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), yet how this shared ligand input is decoded in the heart remains unclear. Previous work established that corticosterone suppresses postnatal cardiomyocyte proliferation through GR. Here we show that corticosteroid responses are governed by a functional GR-MR hierarchy and by cellular context. Genetic or pharmacological GR inhibition redirects corticosterone towards cardiomyocyte proliferation, and MR antagonism or silencing abolishes this effect. GR disruption also enhances aldosterone-induced proliferation in cardiomyocyte-enriched cultures, indicating that GR restrains MR output beyond ligand allocation. However, aldosterone fails to increase cardiomyocyte proliferation in mixed cultures and instead stimulates fibroblast proliferation and activation. By contrast, corticosterone combined with GR inhibition promotes cardiomyocyte proliferation without inducing stromal proliferation or profibrotic activation. Both treatments induce MR nuclear localisation in fibroblasts, showing that their divergent stromal effects arise despite comparable receptor nuclear engagement. Following myocardial infarction, circulating corticosterone increases and GR inhibition enhances cardiomyocyte MR nuclear localisation. In adult murine myocardium, corticosterone plus GR antagonism increases cardiomyocyte cell-cycle activity in an MR-dependent manner, with analogous responses observed in porcine and human myocardium. These findings identify hierarchical and context-dependent GR-MR signalling as a mechanism of corticosteroid decoding and a potential route to cardiac regeneration.
Authors 16
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Affiliation as printed
Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
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Affiliation as printed
Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
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Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences
Affiliation as printed
Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands
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Affiliation as printed
Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
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Affiliation as printed
Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
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Leiden University Medical Center · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands
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IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola
Affiliation as printed
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola
Affiliation as printed
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Affiliation as printed
Scientific and Technological Pole, IRCCS MultiMedica, Milan, Italy
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Affiliation as printed
Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
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Affiliation as printed
Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
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Istituto Nazionale Biostrutture e Biosistemi
Affiliation as printed
ELDOR Lab - National Laboratory of Molecular Biology and Stem Cell Engineering, Istituto Nazionale Biostrutture e Biosistemi (INBB), Bologna, Italy
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Istituto Nazionale Biostrutture e Biosistemi
Affiliation as printed
ELDOR Lab - National Laboratory of Molecular Biology and Stem Cell Engineering, Istituto Nazionale Biostrutture e Biosistemi (INBB), Bologna, Italy
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IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola · University of Bologna
Affiliation as printed
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences
Affiliation as printed
Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, the Netherlands
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IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola · University of Bologna
Affiliation as printed
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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