Biology subjects

Ventura, C.

Publications and source records attributed to Ventura, C..

4 recordsLinked to original sources

bioRxiv2026

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.

molecular biology↗

bioRxiv2026

Hazard characterization of Alternaria toxins - filling data gaps on in vitro genotoxicity.

Alternaria toxins are naturally occurring food contaminants with limited and often inconsistent genotoxicity and mutagenicity data. Within the European Partnership for the Assessment of Risks from Chemicals (PARC), an OECD-aligned in vitro testing strategy was applied to fill existing data gaps and to characterize the genotoxic potential of major Alternaria toxins using high-purity test materials. Mutagenicity was assessed using bacterial reverse mutation test (OECD TG 471) and SOS/umu assay, while chromosomal damage was assessed using the in vitro micronucleus (MN) assay (OECD TG 487) in TK6 and HepG2 cells, complemented by fluorescence in situ hybridization (FISH) and {gamma}H2AX assay in HepaRG cells. Alternariol (AOH), alternariol monomethyl ether (AME), and altertoxin-I (ATX-I) showed clear mutagenicity in bacteria, whereas altenuene (ALT), tenuazonic acid (TeA), and tentoxin (TEN) were negative under the tested conditions. In mammalian cells, AOH, AME, and ATX-I induced MN formation in TK6 cells at concentrations [≥]5.5 {micro}M, [≥]2.5 {micro}M, and [≥]0.21 {micro}M, respectively, with FISH analysis supporting a clastogenic mode of action. In HepG2 cells, all tested toxins induced chromosomal damage, with effect threshold ranging from [≥]6.25 {micro}M (AOH) to [≥]50 {micro}M (TeA). {gamma}H2AX induction confirmed DNA damage for AOH and ATX-I, and at higher concentrations for TeA (1000 {micro}M). Overall, the data indicate clear in vitro genotoxic potential for AOH, AME, and ATX-I and provide evidence of chromosomal damage for ALT, TEN, and TeA, thereby reducing critical data gaps for hazard assessment.

pharmacology and toxicology↗

bioRxiv2025

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

Severe myocardial injuries in mammals lead to cardiomyocyte loss and heart failure. Activation of Glucocorticoid Receptor (GR) by endogenous glucocorticoids limit cardiomyocyte proliferation and cardiac regeneration. Here, we reveal that glucocorticoids suppress the proliferative response of cardiomyocytes to a diverse range of regenerative factors, including Neuregulin 1 (NRG1), FGF1, IGF2, IGF1, BMP7, Oncostatin M (OSM), LIF, RANKL, IL6, IL13, IL4, and IL1-beta. Transcriptomic analyses revealed that glucocorticoids-GR axis induces the expression of MAPK/ERK pathway inhibitors ERRFI1/MIG6 and DUSP1. Using NRG1 as a model system for cardiac regenerative factors, we demonstrate that glucocorticoids suppress growth factor-induced ERK activation, nuclear translocation, and transcriptional output. Knockdown experiments confirmed that ERRFI1 and DUSP1 are key mediators of glucocorticoid-mediated suppression of cardiomyocyte proliferation induced by growth factors. The cardiac expression of GR target genes, including Dusp1 and Errfi1, increases during early postnatal development, coinciding with the transition to post-mitotic cardiomyocytes. In juvenile and adult stage, regenerative growth factors failed to activate MAPK/ERK pathway and induce proliferation effectively; however, DUSP1 inhibition rescues these responses. Consistently, GR antagonization during early postnatal development preserved MAPK/ERK pathway activity. Importantly, GR antagonization or deletion reinstated growth-factor-induced proliferation of postmitotic cardiomyocytes. Finally, GR antagonization enhanced the in vivo effectiveness of growth factor-based regenerative therapy in an adult mouse model of myocardial injury, enhancing cardiomyocyte proliferation and cardiac function. These findings reveal a previously unrecognized mechanism by which systemic hormones, specifically glucocorticoids, regulate the regenerative potential of cardiac paracrine factors. This study highlights transient glucocorticoid inhibition as a promising strategy to enhance the therapeutic efficacy of growth factor-based cardiac regenerative approaches. HighlightsO_LIPhysiological glucocorticoids suppress the proliferative response of cardiomyocytes to regenerative growth factors and cytokines. C_LIO_LIGlucocorticoids inhibit growth factor-induced MAPK/ERK activation in cardiomyocytes by upregulating the expression of negative regulators DUSP1 and ERRFI1. C_LIO_LIIncreased glucocorticoid-induced expression of DUSP1 and ERRFI1 during early postnatal development impairs the mitogenic activity of cardiac regenerative factors. C_LIO_LIGR antagonization restores growth factor-induced MAPK signaling and mitogenic activity in postmitotic cardiomyocytes and enhances the efficacy of growth factor-based regenerative therapies following myocardial injury. C_LI

cell biology↗

bioRxiv2023

BMP7 promotes cardiomyocyte regeneration

Zebrafish has a remarkable and lifelong ability for cardiac regeneration after severe damage, whereas mammals lose their innate capacity for heart regeneration during early postnatal development. This study aimed to investigate whether the decreased production of growth factors during postnatal mammalian development contributes to the exit of cardiomyocytes from the cell cycle and the reduction in cardiac regenerative ability. We identified growth factors with declining expression levels during early postnatal life in the mouse model and assessed the pro-proliferative ability of these factors on neonatal murine primary cardiomyocytes in vitro. Our findings confirmed the previously reported pro-proliferative effects of NRG1, IL1b, RANKL, IGF2 and IL6, while also identifying novel potential pro-regenerative growth factors. Among them, BMP7 exhibited the most pronounced efficacy. Bmp7 knockdown interfered with the proliferation of neonatal mouse cardiomyocytes in culture and adult bmp7 mutant zebrafish displayed reduced cardiomyocyte proliferation during heart regeneration, indicating that Bmp7 is crucial for cardiomyocyte proliferation in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression was sufficient to boost cardiomyocyte cycling in regenerating zebrafish hearts, while BMP7 administration stimulated mouse cardiomyocyte cycling at postnatal-day-7, when cardiomyocytes ceased to proliferate, and enhanced cardiomyocyte regeneration in vivo in adult mice following myocardial infarction. Mechanistically, BMP7-induced proliferation was mediated by type I BMP receptors BMPR1A and ACVR1, and type II receptors ACVR2A and BMPR2. Downstream signalling involved SMAD5, ERK and AKT. In conclusion, the administration of BMP7 holds promise as a strategy to stimulate heart regeneration following cardiac injury.

molecular biology↗