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

Sean A Hardy; Laura Liesinger; Ralph Patrick; Maria Poettler; Lavinia Rech; Juergen Gindlhuber; Nishani S Mabotuwana; DiyaaEldin Ashour; Verena Stangl; Mark Bigland; Lucy A Murtha; Malcolm R Starkey; Daniel Scherr; Philip M Hansbro; Gerald Hoefler; Gustavo Campos Ramos; Clement Cochain; Richard P Harvey; Ruth Birner-Gruenberger; Andrew J Boyle; Peter P Rainer

doi:10.1016/j.jacbts.2023.05.010

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

JACC Basic Transl Sci. 2023 Aug 16;8(12):1539-1554. doi: 10.1016/j.jacbts.2023.05.010. eCollection 2023 Dec.

Authors

Sean A Hardy^{1

2

3}, Laura Liesinger^{4

5}, Ralph Patrick^{6

7}, Maria Poettler¹, Lavinia Rech^{1

8}, Juergen Gindlhuber⁹, Nishani S Mabotuwana^{1

2

3}, DiyaaEldin Ashour¹⁰, Verena Stangl⁴, Mark Bigland^{2

3}, Lucy A Murtha^{2

3}, Malcolm R Starkey¹¹, Daniel Scherr¹, Philip M Hansbro¹², Gerald Hoefler⁴, Gustavo Campos Ramos^{10

13}, Clement Cochain^{10

14}, Richard P Harvey^{6

7

15}, Ruth Birner-Gruenberger^{4

5

16}, Andrew J Boyle^{2

3

17}, Peter P Rainer^{1

16

18}

Affiliations

¹ Department of Internal Medicine and University Heart Center, Division of Cardiology, Medical University of Graz, Graz, Austria.
² School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
³ Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
⁴ Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria.
⁵ Institute of Chemical Technologies and Analytical Chemistry, Technische Universität Wien, Vienna, Austria.
⁶ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
⁷ St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia.
⁸ Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁹ Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
¹⁰ Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany.
¹¹ Department of Immunology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
¹² Centre for Inflammation, Centenary Institute, and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, New South Wales, Australia.
¹³ Department of Internal Medicine 1, University Hospital of Würzburg, Würzburg, Germany.
¹⁴ Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
¹⁵ School of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW Sydney, Sydney, Australia.
¹⁶ BioTechMed Graz, Graz, Austria.
¹⁷ Department of Cardiovascular Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia.
¹⁸ Department of Medicine, St. Johann in Tirol General Hospital, St. Johann in Tirol, Austria.

Abstract

Irreversible fibrosis is a hallmark of myocardial infarction (MI) and heart failure. Extracellular matrix protein-1 (ECM-1) is up-regulated in these hearts, localized to fibrotic, inflammatory, and perivascular areas. ECM-1 originates predominantly from fibroblasts, macrophages, and pericytes/vascular cells in uninjured human and mouse hearts, and from M1 and M2 macrophages and myofibroblasts after MI. ECM-1 stimulates fibroblast-to-myofibroblast transition, up-regulates key fibrotic and inflammatory pathways, and inhibits cardiac fibroblast migration. ECM-1 binds HuCFb cell surface receptor LRP1, and LRP1 inhibition blocks ECM-1 from stimulating fibroblast-to-myofibroblast transition, confirming a novel ECM-1-LRP1 fibrotic signaling axis. ECM-1 may represent a novel mechanism facilitating inflammation-fibrosis crosstalk.

Keywords: extracellular matrix; fibroblasts; fibrosis; heart; inflammation; myocardial infarction.