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Heart, Lung and Circulation
Abstract| Volume 31, SUPPLEMENT 3, S311, 2022

Extracellular Matrix Protein 1 as a Mediator of Inflammation-Induced Fibrosis After Myocardial Infarction

  • S. Hardy
    Affiliations
    School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia

    Department of Internal Medicine and University Heart Center, Division of Cardiology, Medical University of Graz, Graz, Austria

    Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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  • R. Patrick
    Affiliations
    Victor Chang Cardiac Research Institute, Sydney, NSW, Australia

    St. Vincent’s Clinical School, Faculty of Medicine, UNSW, Sydney, NSW, Australia
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  • L. Liesinger
    Affiliations
    Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
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  • M. Pöttler
    Affiliations
    Department of Internal Medicine and University Heart Center, Division of Cardiology, Medical University of Graz, Graz, Austria
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  • L. Rech
    Affiliations
    Department of Internal Medicine and University Heart Center, Division of Cardiology, Medical University of Graz, Graz, Austria
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  • J. Gindlhuber
    Affiliations
    Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria

    Faculty of Technical Chemistry, Institute of Chemical Technologies and Analytics, Technical University of Vienna, Vienna, Austria
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  • N. Mabotuwana
    Affiliations
    School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia

    Department of Internal Medicine and University Heart Center, Division of Cardiology, Medical University of Graz, Graz, Austria

    Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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  • D. Ashour
    Affiliations
    Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany
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  • V. Stangl
    Affiliations
    Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
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  • M. Bigland
    Affiliations
    School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia

    Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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  • L. Murtha
    Affiliations
    School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia

    Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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  • M. Starkey
    Affiliations
    Department of Immunology and Pathology, Central Clinical School, Monash University, Clayton, Vic, Australia
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  • D. Scherr
    Affiliations
    Department of Internal Medicine and University Heart Center, Division of Cardiology, Medical University of Graz, Graz, Austria
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  • P. Hansbro
    Affiliations
    Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, NSW, Australia

    Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, and The University of Newcastle, Callaghan, NSW, Australia
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  • G. Höfler
    Affiliations
    Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
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  • G. Ramos
    Affiliations
    Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany

    Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany
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  • C. Cochain
    Affiliations
    Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany

    Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
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  • R. Harvey
    Affiliations
    Victor Chang Cardiac Research Institute, Sydney, NSW, Australia

    St. Vincent’s Clinical School, Faculty of Medicine, UNSW, Sydney, NSW, Australia

    School of Biotechnology and Biomolecular Science, UNSW, Sydney, NSW, Australia
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  • R. Birner-Gruenberger
    Affiliations
    Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria

    Faculty of Technical Chemistry, Institute of Chemical Technologies and Analytics, Technical University of Vienna, Vienna, Austria
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  • A. Boyle
    Affiliations
    School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia

    Hunter Medical Research Institute, New Lambton Heights, NSW, Australia

    Department of Cardiovascular Medicine, John Hunter Hospital, New Lambton Heights, NSW, Australia
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  • P. Rainer
    Affiliations
    Department of Internal Medicine and University Heart Center, Division of Cardiology, Medical University of Graz, Graz, Austria

    BioTechMed, Graz, Austria
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      Background

      Fibrosis is a hallmark of heart disease, particularly following myocardial infarction (MI) and in heart failure. We previously identified a key role for extracellular matrix protein (ECM1) in wound healing post-MI but the cellular origin and mechanism of ECM1 remained elusive. Here, we investigate the spatiotemporal cellular origin of ECM1 in healthy and diseased human and mouse hearts, and ECM1 dependent human cardiac fibroblast (HuCFb) signalling mechanisms.

      Methods

      ECM1 specific analysis of existing single-cell/-nuclei RNA sequencing data was conducted. ECM1 expression was assessed in non-failing (NF), ischaemic (ICM) and dilated (DCM) failing human heart tissue via immunoblotting (n=8), immunohistochemistry (ICM; n=8, NF; n=4) and mRNA in-situ hybridisation (n=3). HuCFbs were treated with recombinant ECM1 and assessed via phosphoproteomics (n=6), wound healing assay (n=4), MTT assay (n=8), qPCR (n=6).

      Results

      ECM1 originates from fibroblasts, macrophages/monocytes (MΦ/Mo), and pericytes/vascular cells in uninjured human and mouse hearts. In mouse hearts post-MI, ECM1 originates predominantly from M1MΦ/Mo at day-3, and myofibroblasts and M2MΦ’s at day-7, and expression correlated with cell-cell communication, collagen organisation, inflammation, adhesion, and migration. Fittingly, ECM1 expression was upregulated in human ICM (p=0.048) and DCM (p=0.027), localised interstitially to fibrotic, inflammatory, and peri-vascular areas. In vitro, ECM1 inhibited HuCFb migration (p=0.044) and CCL2 mRNA expression, and stimulated inflammatory (IL-6, IL-1β), fibrotic (TGF-β1, Col1a2), and non-canonical Wnt5a mRNA expression (p<0.05). Phosphoproteomics showed ECM1 stimulates HuCFb Rho protein, cell-cell adhesion, and chemotactic signalling pathways.

      Conclusions

      ECM1 may represent a novel mechanism in facilitating inflammation-fibrosis crosstalk post-MI, and a potential therapeutic target.