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.