Dissecting the crosstalk between glucocorticoids and growth factors: implications for cardiac regenerative therapies

Unlike certain lower vertebrates with remarkable regenerative abilities, humans and other mammals face limitations in regenerating tissues and organs. As a result, myocardial injuries in mammals often lead to heart failure, driven by the irreversible death and loss of cardiomyocytes and the heart's insufficient regenerative capacity to replace them. We recently demonstrated that physiological glucocorticoids reduce cardiomyocyte proliferation and regeneration by activating the Glucocorticoid Receptor (GR). Transcriptomic data from cultured cardiomyocytes treated in vitro with glucocorticoids revealed that glucocorticoids induce the expression of DUSP1 and ERRFI1, which are negative regulators of MAPK/ERK signaling. This pathway is pivotal in mediating the cardiac regenerative effect of RTK-dependent growth factors such as NRG1, FGF1, IGF2, IGF1, as well as RTK-independent growth factors and cytokines like BMP7, OSM, LIF, RANKL, IL6, IL13, IL4, and IL1-β. Glucocorticoids inhibited cardiomyocyte proliferation induced by all these regenerative factors. Using NRG1 as the primary model system for cardiac regenerative factors, we demonstrate that glucocorticoids suppress growth factor-induced ERK phosphorylation, nuclear translocation, and the transcription of Immediate Early Genes (IEGs). Importantly, knock-down experiments targeting Dusp1 and Errfi1 confirmed their specific involvement in corticosterone-induced inhibition of growth factor-induced mitogenic potential. We also observed that the expression of GR targets, including the MAP kinase negative regulators Dusp1 and Errfi1, increases during early postnatal development. Notably, GR antagonism during this period preserved MAPK/ERK pathway activity. In line, inhibition of DUSP1 in post-mitotic cardiomyocytes restored growth factor-induced MAPK pathway activation and proliferation. In post-mitotic cardiomyocytes, antagonizing or ablating the glucocorticoid receptor was sufficient to restore NRG1-induced mitogenic capacity. Finally, GR antagonization combined with NRG1 administration induced cardiomyocytes cell cycle activity and preserved cardiac function in adult mouse models of cardiac damage induced by anthracycline administration. We propose the transient inhibition of GCs/GR activity as a promising strategy for enhancing MAPK-based cardiac regenerative therapies.