Glucocorticoid Receptor ablation promotes cardiac regeneration by hampering cardiomyocyte terminal differentiation

Abstract

In mammals, glucocorticoid levels rise dramatically shortly before birth and prepare the foetus for post-natal life by promoting the maturation of the lungs and other organs.However, their impact on cardiac postnatal growth and regenerative plasticity is unknown.Here, we demonstrate that exposure to endogenous glucocorticoids facilitates cell cycle exit and reduces the proliferation of neonatal cardiomyocytes. This cytostatic activity is shared by several synthetic glucocorticoid receptor (GR) agonists routinely used in clinical settings. We also observed that GR levels increase in cardiomyocytes during early post-natal development. Importantly, in vivo cardiomyocyte-specific GR ablation delayed the transition from hyperplastic (increase in cell number) to hypertrophic (increase in cell size) growth. Further, GR ablation partially impaired cardiomyocyte maturation, reducing myofibrils-mitochondria organization along with the expression of genes involved in fatty acid metabolism, mitochondrial respiration and energy transfer from mitochondria to the cytosol. Finally, we show increased cardiomyocyte proliferation in GR ablated juvenile and adult cardiomyocytes in response to myocardial infarction in vivo, thus promoting cardiac tissue regeneration.We suggest that GR antagonization could serve as a strategy for heart regeneration based on endogenous cardiomyocyte renewal.3

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

“…Importantly, a role for physiological glucocorticoids in postnatal cardiomyocyte growth and regenerative plasticity has been recently suggested in the mouse model. Indeed, a physiological increase in GR activation by endogenous glucocorticoids in the early postnatal development concurs to restrain the proliferative ability of neonatal cardiomyocytes [pre-publication by Pianca and colleagues (167)]. Cardiomyocyte-specific GR ablation (GR-cKO) appears sufficient to boost neonatal cardiomyocyte proliferation and to delay the early postnatal transition from hyperplastic to hypertrophic growth along with the maturation of myofibrils-mitochondria organization [pre-publication by Pianca and colleagues (167)].…”

“…Indeed, a physiological increase in GR activation by endogenous glucocorticoids in the early postnatal development concurs to restrain the proliferative ability of neonatal cardiomyocytes [pre-publication by Pianca and colleagues (167)]. Cardiomyocyte-specific GR ablation (GR-cKO) appears sufficient to boost neonatal cardiomyocyte proliferation and to delay the early postnatal transition from hyperplastic to hypertrophic growth along with the maturation of myofibrils-mitochondria organization [pre-publication by Pianca and colleagues (167)]. Further analysis unveiled that GR ablation increases cardiomyocyte replication by regulating the energetic metabolism, favoring glucose catabolism over fatty acid oxidation [pre-publication by Pianca and colleagues (167)].…”

“…Cardiomyocyte-specific GR ablation (GR-cKO) appears sufficient to boost neonatal cardiomyocyte proliferation and to delay the early postnatal transition from hyperplastic to hypertrophic growth along with the maturation of myofibrils-mitochondria organization [pre-publication by Pianca and colleagues (167)]. Further analysis unveiled that GR ablation increases cardiomyocyte replication by regulating the energetic metabolism, favoring glucose catabolism over fatty acid oxidation [pre-publication by Pianca and colleagues (167)]. However, in later stages of postnatal life, no differences in cardiomyocyte proliferation rate were reported in GR ablated compared to control mice (168).…”

“…However, in later stages of postnatal life, no differences in cardiomyocyte proliferation rate were reported in GR ablated compared to control mice (168). Nevertheless, upon myocardial infarction, cardiomyocytes in GR ablated juvenile and adult mice are facilitated to re-enter into the cell cycle and divide, leading to regeneration of the lost cardiac tissue along with reduced scar formation [pre-publication by Pianca and colleagues (167)]. Altogether these results support a model where increased activation of GCs/GR axis restrains the regenerative plasticity of cardiomyocytes.…”

Heart development and regeneration—a multi‐organ effort

“…Cardiomyocyterestricted GR deficiency increases cardiomyocyte selfrenewal in the infarcted juvenile and adult myocardium, suggesting the potential of GR antagonization to promote heart regeneration [23].…”