In mammals, the physiological activation of the glucocorticoid receptor (GR) by glucocorticoids (GCs) promotes the maturation of cardiomyocytes during late gestation, but the effect on postnatal cardiac growth and regenerative plasticity is unclear. Here we demonstrate that the GC–GR axis restrains cardiomyocyte proliferation during postnatal development. Cardiomyocyte- specific GR ablation in conditional knockout (cKO) mice delayed the postnatal cardiomyocyte cell cycle exit, hypertrophic growth and cytoarchitectural maturation. GR-cKO hearts showed increased expression of genes involved in glucose catabolism and reduced expression of genes promoting fatty acid oxidation and mitochondrial respiration. Accordingly, oxygen consump- tion in GR-cKO cardiomyocytes was less dependent on fatty acid oxidation, and glycolysis inhibition reverted GR-cKO effects on cardiomyocyte proliferation. GR ablation or transient pharmacological inhibition after myocardial infarction in juvenile and/ or adult mice facilitated cardiomyocyte survival, cell cycle re-entry and division, leading to cardiac muscle regeneration along with reduced scar formation. Thus, GR restrains heart regeneration and may represent a therapeutic target.

Glucocorticoid receptor antagonization propels endogenous cardiomyocyte proliferation and cardiac regeneration / Nicola Pianca, Francesca Sacchi, Kfir Baruch Umansky, Maila Chirivì, Luisa Iommarini, Silvia Da Pra, Valentina Papa, Chiara Bongiovanni, Carmen Miano, Francesca Pontis, Luca Braga, Riccardo Tassinari, Elvira Pantano, Rahul Shastry Patnala, Martina Mazzeschi, Giovanna Cenacchi, Anna Maria Porcelli, Mattia Lauriola, Carlo Ventura, Mauro Giacca, Roberto Rizzi, Eldad Tzahor, Gabriele D’Uva. - In: NATURE CARDIOVASCULAR RESEARCH. - ISSN 2731-0590. - ELETTRONICO. - 1:7(2022), pp. 617-633. [10.1038/s44161-022-00090-0]

Glucocorticoid receptor antagonization propels endogenous cardiomyocyte proliferation and cardiac regeneration

Francesca Sacchi
Co-primo
;
Luisa Iommarini;Silvia Da Pra;Valentina Papa;Chiara Bongiovanni;Carmen Miano;Francesca Pontis;Riccardo Tassinari;Martina Mazzeschi;Giovanna Cenacchi;Anna Maria Porcelli;Mattia Lauriola;Carlo Ventura;Gabriele D’Uva
Ultimo
2022

Abstract

In mammals, the physiological activation of the glucocorticoid receptor (GR) by glucocorticoids (GCs) promotes the maturation of cardiomyocytes during late gestation, but the effect on postnatal cardiac growth and regenerative plasticity is unclear. Here we demonstrate that the GC–GR axis restrains cardiomyocyte proliferation during postnatal development. Cardiomyocyte- specific GR ablation in conditional knockout (cKO) mice delayed the postnatal cardiomyocyte cell cycle exit, hypertrophic growth and cytoarchitectural maturation. GR-cKO hearts showed increased expression of genes involved in glucose catabolism and reduced expression of genes promoting fatty acid oxidation and mitochondrial respiration. Accordingly, oxygen consump- tion in GR-cKO cardiomyocytes was less dependent on fatty acid oxidation, and glycolysis inhibition reverted GR-cKO effects on cardiomyocyte proliferation. GR ablation or transient pharmacological inhibition after myocardial infarction in juvenile and/ or adult mice facilitated cardiomyocyte survival, cell cycle re-entry and division, leading to cardiac muscle regeneration along with reduced scar formation. Thus, GR restrains heart regeneration and may represent a therapeutic target.
2022
Glucocorticoid receptor antagonization propels endogenous cardiomyocyte proliferation and cardiac regeneration / Nicola Pianca, Francesca Sacchi, Kfir Baruch Umansky, Maila Chirivì, Luisa Iommarini, Silvia Da Pra, Valentina Papa, Chiara Bongiovanni, Carmen Miano, Francesca Pontis, Luca Braga, Riccardo Tassinari, Elvira Pantano, Rahul Shastry Patnala, Martina Mazzeschi, Giovanna Cenacchi, Anna Maria Porcelli, Mattia Lauriola, Carlo Ventura, Mauro Giacca, Roberto Rizzi, Eldad Tzahor, Gabriele D’Uva. - In: NATURE CARDIOVASCULAR RESEARCH. - ISSN 2731-0590. - ELETTRONICO. - 1:7(2022), pp. 617-633. [10.1038/s44161-022-00090-0]
Nicola Pianca, Francesca Sacchi, Kfir Baruch Umansky, Maila Chirivì, Luisa Iommarini, Silvia Da Pra, Valentina Papa, Chiara Bongiovanni, Carmen Miano, Francesca Pontis, Luca Braga, Riccardo Tassinari, Elvira Pantano, Rahul Shastry Patnala, Martina Mazzeschi, Giovanna Cenacchi, Anna Maria Porcelli, Mattia Lauriola, Carlo Ventura, Mauro Giacca, Roberto Rizzi, Eldad Tzahor, Gabriele D’Uva
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/895421
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