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

Nature Cardiovascular Research (2026)Cite this article

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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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Fig. 1: Glucocorticoids suppress the mitogenic activity of cardiac regenerative growth factors and cytokines.
Fig. 2: Glucocorticoids trigger the expression of negative regulators of MAPK-signaling pathway via GR activation.
Fig. 3: Glucocorticoids intercept growth-factor-induced MAPK–ERK signaling activation in cardiomyocytes.
Fig. 4: Increased glucocorticoid-induced DUSP1 and ERRFI1 expression in early postnatal development impairs the mitogenic potential of regenerative factors.
Fig. 5: Inhibition of the glucocorticoid–GR axis rescues the mitogenic potential of regenerative factors in postmitotic cardiomyocytes.
Fig. 6: GR antagonism enhances growth factor-induced cardiomyocyte protection and cell-cycle re-entry as well as heart functional preservation after cardiac damage.
Fig. 7: Schematic diagram of the impact of glucocorticoids on MAPK–ERK signaling cascade activation by growth factor or cytokine signaling in cardiomyocyte protection and regeneration.

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Data availability

The datasets and uncropped scans of figures and extended data generated in this study are available as source data files. RNA-seq data generated in this study (Fig. 2a,b and Supplementary Table 3) were deposited in the Gene Expression Omnibus repository under accession nos. GSE286562 (controls in GSE202968). Published RNA-seq data analyzed in Extended Data Fig. 5d–f are available in the Gene Expression Omnibus repository under accession no. GSE144391 (ref. 68). Published RNA-seq data analyzed in Fig. 4b are available as supplementary information in the original paper69. Source data are provided with this paper.

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Acknowledgements

We acknowledge financial support under the National Recovery and Resilience Plan, Mission 4, Component 2, Investment 1.1, Call for tender no. 1409 published on 14 September 2022 by the Italian Ministry of University and Research (MUR), funded by the European Union (EU)—NextGenerationEU—Project ‘The cardiomyocyte-intrinsic role of the glucocorticoid receptor in cardiac aging’, CUP J53D23018140001 grant assignment decree no. 1369 adopted on 1 September 2023 by the MUR to G.D'U. The research was also supported by the EU’s Horizon 2020 research and innovation program under the ERA-NET on the Cardiovascular Diseases co-fund action to G.D'U. and E.T. (grant no. JCT2016-40-080), Fondazione Carisbo to G.D'U. (grant no. 2023.0210) and by the Italian Ministry of Health (grant no. RC24000858-2795994 ex 2790614 to G.D'U.). The views and opinions expressed are those of the authors only and do not necessarily reflect those of the EU or the European Commission. Neither the EU nor the European Commission can be responsible for them. S.D.P. was supported by a PON Research and Innovation 2014–2020 (FSE React-EU) PhD Scholarship (code no. DOT1303972—CUP J35F21003360006) funded by the MUR under DM 1061/2021, Action IV.4 ‘Doctorates and Research Contracts on Innovation Topics’. E.T. was supported by the European Research Council (ERC AdG, grant no. 788194). C. Batho and R.D. were funded by the British Heart Foundation (grant nos. G114642 and GBP0051 to C.W.). We thank the Centre for Applied Biomedical Research, University of Bologna for technical support.

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Author notes

  1. These authors contributed equally: Silvia Da Pra, Stefano Boriati.

Authors and Affiliations

  1. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

    Silvia Da Pra, Stefano Boriati, Carmen Miano, Francesca Sacchi, Irene Del Bono, Carlo Ventura, Mattia Lauriola & Gabriele D’Uva

  2. Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy

    Silvia Da Pra, Stefano Boriati, Carmen Miano, Francesca Sacchi & Irene Del Bono

  3. Gurdon Institute and Department of Pharmacology, University of Cambridge, Cambridge, UK

    Christopher Batho, Rowda Dahir & Catherine H. Wilson

  4. IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

    Chiara Bongiovanni, Mattia Lauriola & Gabriele D’Uva

  5. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

    Alla Aharonov & Eldad Tzahor

  6. Scientific and Technological Pole, IRCCS MultiMedica, Milan, Italy

    Nicola Pianca

  7. Eldor Lab, Bologna, Italy

    Riccardo Tassinari

  8. National Institute of Biostructures and Biosystems (INBB), Bologna, Italy

    Carlo Ventura

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  1. Silvia Da Pra
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  2. Stefano Boriati
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  16. Gabriele D’Uva
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Contributions

S.D.P., S.B. and G.D’U. conceived and designed the experiments. S.D.P. and S.B. carried out most of the experiments and analyzed the data. S.D.P. and S.B. performed in vivo experiments. S.B. performed echocardiographic analysis. C.M., F.S., C. Bongiovanni, I.D.B., A.A. and N.P. performed immunofluorescence and gene expression analyses. R.T. performed in vitro immunofluorescence image acquisition and time-lapse imaging. S.D.P., S.B. and G.D’U. analyzed RNA-seq data. C. Batho and R.D. designed and synthesized modRNAs. C.V., M.L., E.T. and C.H.W. supervised the experiments performed by their laboratory members. G.D’U. conceptualized the study and supervised the entire project. S.D.P., S.B. and G.D’U. wrote the paper, with editing contributions from all authors.

Corresponding author

Correspondence to Gabriele D’Uva.

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Competing interests

G.D’U., E.T. and A.A. are listed as co-inventors on a patent related to ERBB2-mediated cardiac regeneration (no. US20160326250A1). The other authors declare no competing interests.

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Nature Cardiovascular Research thanks Richard Lee and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Representative images showing cardiomyocyte proliferation after in vitro treatment with regenerative growth factors, as determined by BrdU incorporation assay.

Cardiomyocytes were identified by cardiac Troponin I (cTnI) staining and analysed by immunofluorescence for DNA synthesis (BrdU incorporation assay). White arrows point to proliferating cardiomyocytes; scale bars 50 μm.

Extended Data Fig. 2 Corticosterone impairs phenotypic changes induced by caERBB2 expression.

(a) Analysis of the efficacy of lipofectamine-mediated modRNA transfection of postnatal day 1 (P1) cardiomyocytes cultured in vitro. Cardiomyocytes were identified by cardiac Troponin T (cTnT) staining and transfection was assessed through eGFP expression 24 h after modRNA delivery. A representative figure is provided; scale bar 50 μm; (b-c) Subdivision of Ki67+ postnatal day 1 cardiomyocytes analysed in Fig. 1g into mononucleated (b) and binucleated (c) cells; (d-e) Analysis of area (d) and Troponin T intensity (e) of postnatal day 1 (P1) cardiomyocytes cultured in vitro and transfected for 48 h with a modRNA encoding a constitutively active isoform of ERBB2 (caERBB2) together with corticosterone (CORT, 10−8 M). Cardiomyocytes were identified by cardiac Troponin T (cTnT) staining. Details on the number of replicates and experiments for each panel are provided in Supplementary Table 2. The values are presented as mean (error bars show standard deviation), statistical significance was determined using one-way ANOVA followed by Sidak’s test in (b), (c), (d), and (e) (comparison between pairs of treatments).

Source data

Extended Data Fig. 3 Analysis of hypertrophic changes in cardiomyocytes following in vivo administration of corticosterone in early postnatal life.

(a-i) RT-qPCR analysis of mRNA expression of (a) Myh7, (b) Myh6, (c) Tnni1, (d) Tnni3, (e) Myh7/Myh6, (f) Tnni1/Tnni3, (g) Acta1, (h) Nppa, and (i) Nppb in mouse postnatal day 2-3 (P2-3) heart lysates following in vivo delivery of water-soluble corticosterone-HBC complex (100 µg/ml) in the drinking water of the lactating mother from postnatal day 0–1 to postnatal day 2–3, for a total of 48 h; (j) Cardiomyocyte cross-sectional area evaluation by immunofluorescence analysis of WGA in heart sections of mice at postnatal day 2–3 following in vivo delivery of water-soluble corticosterone-HBC complex (100 µg/ml) in the drinking water of the lactating mother from postnatal day 0–1 to postnatal day 2–3, for a total of 48 h. Representative images are provided. Dashed outlines highlight cross-sectional areas of transversely aligned cardiomyocytes. Scale bars, 30 μm. Details on the number of replicates and experiments for each panel are provided in Supplementary Table 2. The values are presented as mean (error bars show standard deviation), statistical significance was determined using two-sided Student’s t-test in (a) (95% CI: -0.7725 to -0.3350), (b) (95% CI: -0.1838 to 0.1447), (c) (95% CI: -0.3339 to -0.005125), (d) (95% CI: -0.05248 to 0.2029), (e) (95% CI: -0.7746 to -0.3126), (f) (95% CI: -0.4603 to -0.03509), (g) (95% CI: 0.4683 to 1.389), (h) (95% CI: -0.04992 to 1.751), (i) (95% CI: -0.2244 to 0.9094), and (j) (95% CI: -4.281 to 1.119).

Source data

Extended Data Fig. 4 In vitro analysis of the efficacy of Errfi1 and Dusp1 gene knockdown in neonatal cardiomyocyte cultures.

(a-b) mRNA expression levels of (a) Errfi1 and (b) Dusp1 in cultured postnatal day 1 (P1) cardiomyocytes following siRNA delivery for 48 h. A pool of non-targeting scramble siRNAs (siSCR) was used as a negative transfection control; (c) Protein expression levels of ERRFI1 and DUSP1 from cultured postnatal day 1 (P1) cardiomyocytes following siRNA delivery for 72 h. A pool of non-targeting scramble siRNAs (siSCR) was used as a negative transfection control; (d) Schematic illustration of experimental set-up in Fig. 3b and Fig. 3d, e. Time-course experiments were performed in whole-cell protein and RNA lysates, with corticosterone administered 6 h before NRG1 treatment for 30, 60, and 120 min. Details on the number of replicates and experiments for each panel are provided in Supplementary Table 2. In all panels, numerical data are presented as mean (error bars show standard deviation). Statistical significance was determined using two-sided Student’s t-test in (a) (95% CI: -0.8423 to -0.2226) and (b) (95% CI: -0.7860 to -0.02741 for siDUSP1).

Source data

Extended Data Fig. 5 Activation of NRG1/ERBB2 signalling leads to the expression of IEGs in cardiomyocytes.

(a-c) RT-qPCR analysis of IEGs (Immediate Early Genes), namely (a) Fos, (b) Junb, and (c) Egr1, upon treatment with NRG1 (100 ng/ml) for 30, 60 and 120 min. (d-f) Analysis of (d) Fos, (e) Junb and (f) Egr1 expression from RNA-sequencing data of cardiac tissue of a mouse model with cardiomyocyte-restricted overexpression of a constitutively active ERBB2 (caERBB2) isoform (Aharonov et al.68). Details on the number of replicates and experiments for each panel are provided in Supplementary Table 2. In all panels, numerical data are presented as mean (error bars show standard deviation). Statistical significance was determined by one way ANOVA followed by Tukey’s test in (a-c) and by two-sided Student’s t-test in (d) (95% CI: 30.90 to 248.8), (e) (95% CI: 267.4 to 779.7) and (f) (95% CI: 1618 to 3970).

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Extended Data Fig. 6 Dusp1 knockdown abolishes the ability of corticosterone to repress the proliferative potential of BMP7, FGF1 and OSM.

Analysis of cell proliferation by BrdU assay in neonatal (postnatal day 1 - P1) cardiomyocytes cultured in vitro following knock-down of Dusp1 for 48 h with/without subsequent stimulation with BMP7, FGF1 or OSM (10 ng/ml), and/or CORT (10−8 M). A pool of non-targeting scramble siRNAs (siSCR) was used as a negative transfection control. Cardiomyocytes were identified by cTnI staining and analysed by immunofluorescence for DNA synthesis (BrdU incorporation assay). Details on the number of replicates and experiments for each panel are provided in Supplementary Table 2. The values are presented as mean (error bars show standard deviation), statistical significance was determined using one-way ANOVA followed by Sidak’s test (comparison between pairs of treatments).

Source data

Extended Data Fig. 7 Glucocorticoid receptor antagonism does not increase the mitogenic activity of NRG1 in postnatal day 1 cardiomyocytes.

Analysis of cell proliferation by BrdU assay in neonatal (postnatal day 1 - P1) cardiomyocytes cultured in vitro following stimulation with GR antagonist RU486 (10−7 M), alone or in combination with NRG1 (100 ng/ml). Cardiomyocytes were identified by cTnI staining and analysed by immunofluorescence for DNA synthesis (BrdU incorporation assay). Representative pictures are provided; arrows point at proliferating cardiomyocyte; scale bars 50 mm. Details on the number of replicates and experiments for each panel are provided in Supplementary Table 2. The values are presented as mean (error bars show standard deviation), statistical significance was determined using one-way ANOVA followed by Sidak’s test (comparison between pairs of treatments).

Source data

Extended Data Fig. 8 Absence of overt cardiomyocyte apoptosis after three weeks of doxorubicin administration.

Analysis of caspase-3 activation (cleaved caspase-3) in heart sections from untreated control animals and from doxorubicin (DOXO)-treated animals, analyzed 21 days after the first DOXO administration. Cardiomyocytes were identified by cardiac Troponin T (cTnT) staining. Representative confocal pictures are provided; scale bars 50 μm.

Extended Data Fig. 9 Echocardiographic evaluation of additional morphological parameters of the in vivo mouse model of anthracycline-induced cardiotoxicity.

Analysis of (a) left ventricular anterior wall thickness at systole (LVAWs), (b) left ventricular end-systolic volume (LVESV), and (c) left ventricular end-diastolic volume (LVEDV) in adult mice at baseline and treated with doxorubicin (DOXO) alone or co-treated with NRG1, RU486, or NRG1 + RU486, 21 days after first DOXO injection. Details on the number of replicates and experiments for each panel are provided in Supplementary Table 2. The values are presented as mean (error bars show standard deviation), statistical significance was determined using one-way ANOVA followed by Sidak’s test in all panels (comparison between pairs of treatments).

Source data

Supplementary information

Reporting Summary

Supplementary Video 1

Time-lapse imaging of cardiomyocyte division after TMRE staining.

Supplementary Tables

Supplementary Table 1 Open reading frame (ORF), T7 promoter and poly(A) tail sequences used for modRNA synthesis. Supplementary Table 2 Details on the number of replicates and independent experiments for each panel shown in the manuscript. Supplementary Table 3 List of GR target genes in cardiomyocytes. List of significantly upregulated genes (log(fold-change) > 0, Padj < 0.05) by RNA-seq analysis of cultured neonatal cardiomyocytes treated in vitro with corticosterone (10−6 M). Supplementary Table 4 List of primers used in this manuscript.

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Da Pra, S., Boriati, S., Miano, C. et al. Harnessing glucocorticoid receptor antagonism to enhance the efficacy of cardiac regenerative growth factors and cytokines. Nat Cardiovasc Res (2026). https://doi.org/10.1038/s44161-026-00776-9

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