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Galectin-3 interferes with tissue repair and promotes cardiac dysfunction and comorbidities in a genetic heart failure model

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Abstract

Galectin-3, a biomarker for heart failure (HF), has been associated with myocardial fibrosis. However, its causal involvement in HF pathogenesis has been questioned in certain models of cardiac injury-induced HF. To address this, we used desmin-deficient mice (des−/−), a model of progressive HF characterized by cardiomyocyte death, spontaneous inflammatory responses sustaining fibrosis, and galectin-3 overexpression. Genetic ablation or pharmacological inhibition of galectin-3 led to improvement of cardiac function and adverse remodeling features including fibrosis. Over the course of development of des−/− cardiomyopathy, monitored for a period of 12 months, galectin-3 deficiency specifically ameliorated the decline in systolic function accompanying the acute inflammatory phase (4-week-old mice), whereas a more pronounced protective effect was observed in older mice, including the preservation of diastolic function. Interestingly, the cardiac repair activities during the early inflammatory phase were restored under galectin-3 deficiency by increasing the proliferation potential and decreasing apoptosis of fibroblasts, while galectin-3 absence modulated macrophage–fibroblast coupled functions and suppressed both pro-fibrotic activation of cardiac fibroblasts and pro-fibrotic gene expression in the des−/− heart. In addition, galectin-3 also affected the emphysema-like comorbid pathology observed in the des−/− mice, as its absence partially normalized lung compliance. Collectively galectin-3 was found to be causally involved in cardiac adverse remodeling, inflammation, and failure by affecting functions of cardiac fibroblasts and macrophages. In concordance with this role, the effectiveness of pharmacological inhibition in ameliorating cardiac pathology features establishes galectin-3 as a valid intervention target for HF, with additive benefits for treatment of associated comorbidities, such as pulmonary defects.

Graphical abstract

Schematic illustrating top to bottom, the detrimental role of galectin-3 (Gal3) in heart failure progression: desmin deficiency-associated spontaneous myocardial inflammation accompanying cardiac cell death (reddish dashed border) is characterized by infiltration of macrophages (round cells) and up-regulation of Lgals3 (encoding secretable galectin-3, green) and detrimental macrophage-related genes (Ccr2 and Arg1). In this galectin-3-enriched milieu, the early up-regulation of profibrotic gene expression (Tgfb1, Acta2, Col1a1), in parallel to the suppression of proliferative activities and a potential of senescence induction by cardiac fibroblasts (spindle-like cells), collectively promote des−/− cardiac fibrosis and dysfunction establishing heart failure (left panel). Additionally, galectin-3+ macrophage-enrichment accompanies the development of emphysema-like lung comorbidities. In the absence of galectin-3 (right panel), the effect of macrophage–fibroblast dipole and associated events are modulated (grey color depicts reduced expression or activities) leading to attenuated cardiac pathology in the des−/−Lgals3−/− mice. Pulmonary comorbidities are also limited.

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Availability of data and material

All data and material supporting the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

We acknowledge Aris Charonis, Argyris Efstratiadis and Dimitris Beis for helpful discussions and antibodies provided, Stamatis Pagakis, Dimosthene Mitrossilis and Eleni Rigana for help with image analysis and confocal microscopy, Anastasia Apostolidou for FACSAria sorting, Niki Karagianni, Maria Platounari, Pagona Karvouni, Lorentsa Tsansizi, Alkistis Kapelouzou, Ioanna Kostavasili and Anna Agapaki for assistance.

Funding

Supported by a Hellenic Cardiology Society grant 2010–13/151 (SP) and the Synergasia ESPA 09SYN-21–965 grant from the Greek General Secretariat for Research and Technology (G.S.R.T.) – Ministerium of Education (YC).

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Authors and Affiliations

  1. Center of Basic Research, Biomedical Research Foundation Academy of Athens, 11527, Athens, Greece

    Fani Vlachou, Konstantina Stathopoulou, Konstantinos Ntatsoulis, Yassemi Capetanaki & Stelios Psarras

  2. Center of Clinical, Experimental and Translational Research, Biomedical Research Foundation Academy of Athens, 11527, Athens, Greece

    Aimilia Varela, Evgenia Synolaki, Paschalis Sideras & Constantinos H. Davos

  3. Institute of Biosciences and Applications, NCSR Demokritos, 153 41, Athens, Greece

    Harris Pratsinis & Dimitris Kletsas

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  1. Fani Vlachou
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Contributions

FV, KS, KN and SP performed experiments, EV performed echocardiography, ES performed lung mechanics experiments and HP performed BrdU and assisted with cardiac fibroblast apoptosis and ex vivo aging experiments. SP designed the study and prepared the manuscript. All the authors provided critical input, reviewed the manuscript, contributed to the discussion/interpretation of the obtained results, and approved the final version.

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Correspondence to Stelios Psarras.

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Vlachou, F., Varela, A., Stathopoulou, K. et al. Galectin-3 interferes with tissue repair and promotes cardiac dysfunction and comorbidities in a genetic heart failure model. Cell. Mol. Life Sci. 79, 250 (2022). https://doi.org/10.1007/s00018-022-04266-6

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  • DOI: https://doi.org/10.1007/s00018-022-04266-6

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