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