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

Myocardial injuries lead to cardiomyocyte loss and heart failure. Endogenous glucocorticoids, via the glucocorticoid receptor (GR), limit cardiomyocyte regeneration. Here we show that glucocorticoids suppress mammalian (murine) cardiomyocyte proliferative response to regenerative growth factors and cytokines. GR activation in neonatal cardiomyocytes upregulated MAPK-ERK inhibitors ERRFI1 and DUSP1. Using neuregulin 1 as a model, we demonstrated that glucocorticoids inhibit growth-factor-induced ERK activation, nuclear translocation and transcriptional output. Errfi1 and Dusp1 knockdown restored growth-factor-induced proliferation of glucocorticoid-exposed cardiomyocytes. Cardiac expression of DUSP1 and ERRFI1 increased postnatally, coinciding with regenerative capacity decline. In juvenile and adult cardiomyocytes, regenerative growth factors failed to induce the MAPK-ERK pathway and proliferation; however, DUSP1 inhibition restored these responses. GR antagonism enhanced growth-factor-induced cardiomyocyte protection, proliferation and cardiac function after adult myocardial injury. These findings reveal the emergence of a postnatal systemic brake on cardiomyocyte proliferative response to growth factors and support GR inhibition as a strategy to enhance growth-factor-based regenerative therapies.