March 3, 2026Nature Cardiovascular Research1 citations

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

SPSilvia Da PraUniversity of Bologna SBStefano BoriatiUniversity of Bologna CMCarmen MianoUniversity of Bologna

Key Result

Glucocorticoid receptor antagonism enhances the efficacy of regenerative growth factors, improving cardiomyocyte protection, proliferation, and cardiac function after adult myocardial injury.

Key Points

Antagonizing glucocorticoid receptors significantly boosts cardiomyocyte proliferation and protection following myocardial injury, indicating a potential breakthrough in cardiac therapies.
Inhibition of DUSP1 restored the proliferative response in glucocorticoid-exposed cardiomyocytes, highlighting its role as a therapeutic target.
The study reveals that endogenous glucocorticoids limit cardiomyocyte regeneration by activating GR, which inhibits critical signaling pathways like MAPK-ERK for growth factors and cytokines. In juvenile and adult cardiomyocytes, regenerative potential declines, but GR antagonism can restore their response to growth factors.

Structured PICO

Does glucocorticoid receptor antagonism enhance the efficacy of cardiac regenerative growth factors in murine models of myocardial injury?

Population

Mammalian (murine) cardiomyocytes (neonatal, juvenile, and adult) and adult murine myocardial injury model

Intervention

Glucocorticoid receptor (GR) antagonism or DUSP1 inhibition combined with regenerative growth factors (e.g., neuregulin 1)

Comparator

Regenerative growth factors alone or glucocorticoid exposure

Outcome

Cardiomyocyte proliferative response, MAPK-ERK pathway activation, cardiomyocyte protection, and cardiac function after injurysurrogate

Glucocorticoid receptor antagonism removes a postnatal systemic brake on cardiomyocyte proliferation, enhancing the efficacy of growth-factor-based regenerative therapies in preclinical models.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

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.

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