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 J. Bigland, Lucy A. Murtha, Malcolm R. Starkey, Daniel Scherr, Philip M. Hansbro, Gerald Höefler, Gustavo Ramos, Clément Cochain, Richard P. Harvey, Ruth Birner‐Gruenberger, Andrew Boyle, Peter P. Rainer
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.