Biology subjects

Pianca, N.

Publications and source records attributed to Pianca, N..

3 recordsLinked to original sources

bioRxiv2026

Hierarchical and context-dependent GR-MR signalling governs endogenous corticosteroid decoding in the heart

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.

molecular biology↗

bioRxiv2025

Harnessing glucocorticoid receptor antagonization to enhance the efficacy of cardiac regenerative growth factors and cytokines

Severe myocardial injuries in mammals lead to cardiomyocyte loss and heart failure. Activation of Glucocorticoid Receptor (GR) by endogenous glucocorticoids limit cardiomyocyte proliferation and cardiac regeneration. Here, we reveal that glucocorticoids suppress the proliferative response of cardiomyocytes to a diverse range of regenerative factors, including Neuregulin 1 (NRG1), FGF1, IGF2, IGF1, BMP7, Oncostatin M (OSM), LIF, RANKL, IL6, IL13, IL4, and IL1-beta. Transcriptomic analyses revealed that glucocorticoids-GR axis induces the expression of MAPK/ERK pathway inhibitors ERRFI1/MIG6 and DUSP1. Using NRG1 as a model system for cardiac regenerative factors, we demonstrate that glucocorticoids suppress growth factor-induced ERK activation, nuclear translocation, and transcriptional output. Knockdown experiments confirmed that ERRFI1 and DUSP1 are key mediators of glucocorticoid-mediated suppression of cardiomyocyte proliferation induced by growth factors. The cardiac expression of GR target genes, including Dusp1 and Errfi1, increases during early postnatal development, coinciding with the transition to post-mitotic cardiomyocytes. In juvenile and adult stage, regenerative growth factors failed to activate MAPK/ERK pathway and induce proliferation effectively; however, DUSP1 inhibition rescues these responses. Consistently, GR antagonization during early postnatal development preserved MAPK/ERK pathway activity. Importantly, GR antagonization or deletion reinstated growth-factor-induced proliferation of postmitotic cardiomyocytes. Finally, GR antagonization enhanced the in vivo effectiveness of growth factor-based regenerative therapy in an adult mouse model of myocardial injury, enhancing cardiomyocyte proliferation and cardiac function. These findings reveal a previously unrecognized mechanism by which systemic hormones, specifically glucocorticoids, regulate the regenerative potential of cardiac paracrine factors. This study highlights transient glucocorticoid inhibition as a promising strategy to enhance the therapeutic efficacy of growth factor-based cardiac regenerative approaches. HighlightsO_LIPhysiological glucocorticoids suppress the proliferative response of cardiomyocytes to regenerative growth factors and cytokines. C_LIO_LIGlucocorticoids inhibit growth factor-induced MAPK/ERK activation in cardiomyocytes by upregulating the expression of negative regulators DUSP1 and ERRFI1. C_LIO_LIIncreased glucocorticoid-induced expression of DUSP1 and ERRFI1 during early postnatal development impairs the mitogenic activity of cardiac regenerative factors. C_LIO_LIGR antagonization restores growth factor-induced MAPK signaling and mitogenic activity in postmitotic cardiomyocytes and enhances the efficacy of growth factor-based regenerative therapies following myocardial injury. C_LI

cell biology↗

bioRxiv2020

Glucocorticoid Receptor ablation promotes cardiac regeneration by hampering cardiomyocyte terminal differentiation

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.

cell biology↗