bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.06.16.448655

EPAC1 Inhibition Protects the Heart from Doxorubicin-Induced Toxicity

Mazevet, M.·Ribeiro, M.·Belhadef, A.·Dayde, D.·Llach, A.·Laudette, M.·Belleville, T.·Mateo, P.·Gressette, M.·Lefebvre, F.·Chen, J.·Bachelot-Loza, C.·Rucker-Martin, C.·Lezoualch, F.·Crozatier, B.·Benitah, J.-P.·Vozenin, M.-C.·Fischmeister, R.·Gomez, A.-M.·Lemaire, C.·Morel, E.
View original source ↗Export metadata ↓

Abstract

Anthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the Exchange Protein directly Activated by cAMP (EPAC) in Dox-induced cardiotoxicity and the potential cardioprotective effects of EPAC inhibition. We show that Dox induces DNA damage and cardiomyocyte cell death with apoptotic features. Dox also led to an increase in both cAMP concentration and EPAC1 activity. The pharmacological inhibition of EPAC1 (with CE3F4) but not EPAC2 alleviated the whole Dox-induced pattern of alterations. When administered in vivo, Dox-treated WT mice developed a dilated cardiomyopathy which was totally prevented in EPAC1 KO mice. Moreover, EPAC1 inhibition potentiated Dox-induced cell death in several human cancer cell lines. Thus, EPAC1 inhibition appears as a potential therapeutic strategy to limit Dox-induced cardiomyopathy without interfering with its antitumoral activity.

Source connections

Explore related subjects

pathologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Mazevet, M., Ribeiro, M., Belhadef, A., Dayde, D., Llach, A., Laudette, M., Belleville, T., Mateo, P., Gressette, M., Lefebvre, F., Chen, J., Bachelot-Loza, C., Rucker-Martin, C., Lezoualch, F., Crozatier, B., Benitah, J.-P., Vozenin, M.-C., Fischmeister, R., Gomez, A.-M., Lemaire, C., Morel, E.. 2021-06-17. EPAC1 Inhibition Protects the Heart from Doxorubicin-Induced Toxicity. https://doi.org/10.1101/2021.06.16.448655

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗
bioRxiv2023

Integrating cellular graph embeddings with tumor morphological features to predict in-silico spatial transcriptomics from H&E images

Spatial transcriptomics allows precise RNA abundance measurement at high spatial resolution, linking cellular morphology with gene expression. We present a novel deep learning algorithm predicting local gene expression from histopathology images. Our approach employs a graph isomorphism neural network capturing cell-to-cell interactions in the tumor microenvironment and a Vision Transformer (CTransPath) for obtaining the tumor morphological features. Using a dataset of 30,612 spatially resolved gene expression profiles matched with histopathology images from 23 breast cancer patients, we identify 250 genes, including established breast cancer biomarkers, at a 100 {micro}m resolution. Additionally, we co-train our algorithm on spatial spot-level transcriptomics from 10x Visium breast cancer data along with another variant of our algorithm on TCGA-BRCA bulk RNA Seq. data, yielding mutual benefits and enhancing predictive accuracy on both these datasets. This work enables image-based screening for molecular biomarkers with spatial variation, promising breakthroughs in cancer research and diagnostics.

pathology↗
bioRxiv2023

Small but significant genetic differentiation among populations of Phyllachora maydis in the midwestern United States revealed by microsatellite (SSR) markers.

Phyllachora maydis Maubl, the causal pathogen of tar spot of corn (Zea mays L.), has emerged recently in the United States and Canada. Studies related to its genetic diversity and population structure are limited and are necessary to improve our understanding of this pathogens biology, ecology, epidemiology, and evolutionary potential within this region. This study developed and used 13 microsatellites (SSR markers) to assess the genetic population structure, diversity, gene flow and reproductive mode of 181 P. maydis samples across five states in the Midwest U.S. The polymorphic information content (PIC) of loci ranged from 0.32 to 0.72 per locus, indicating their high utility for assessing the dynamics of P. maydis populations. Analysis of molecular variance (AMOVA) detected a significantly low, but statistically significant genetic differentiation (FST = 0.15) among populations, where 85% of the variance resided within populations. P. maydis populations were highly diverse (He = 0.55), with moderate gene flow (Nm = 2.80), and showed evidence of sexual recombination ([r]d; p = > 0.001). Structure analysis showed the samples were not geographically structured but rather grouped into two genetic clusters (k =2) of severe genetic admixture suggesting possible long-distance dispersal of aerial spores or infected corn materials among the five Midwest states. Both principal coordinate analysis (PCoA) and discriminate analysis of principal component (DAPC) supported the STRUCTURE analysis of the two clusters. These 13 highly polymorphic molecular markers could be used for future investigations of this pathogens population dynamics within the U.S., and possibly populations outside.

pathology↗