PMID- 30789914 OWN - NLM STAT- MEDLINE DCOM- 20191113 LR - 20200309 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 14 IP - 2 DP - 2019 TI - Novel role of extracellular matrix protein 1 (ECM1) in cardiac aging and myocardial infarction. PG - e0212230 LID - 10.1371/journal.pone.0212230 [doi] LID - e0212230 AB - INTRODUCTION: The prevalence of heart failure increases in the aging population and following myocardial infarction (MI), yet the extracellular matrix (ECM) remodeling underpinning the development of aging- and MI-associated cardiac fibrosis remains poorly understood. A link between inflammation and fibrosis in the heart has long been appreciated, but has mechanistically remained undefined. We investigated the expression of a novel protein, extracellular matrix protein 1 (ECM1) in the aging and infarcted heart. METHODS: Young adult (3-month old) and aging (18-month old) C57BL/6 mice were assessed. Young mice were subjected to left anterior descending artery-ligation to induce MI, or transverse aortic constriction (TAC) surgery to induce pressure-overload cardiomyopathy. Left ventricle (LV) tissue was collected early and late post-MI/TAC. Bone marrow cells (BMCs) were isolated from young healthy mice, and subject to flow cytometry. Human cardiac fibroblast (CFb), myocyte, and coronary artery endothelial & smooth muscle cell lines were cultured; human CFbs were treated with recombinant ECM1. Primary mouse CFbs were cultured and treated with recombinant angiotensin-II or TGF-beta1. Immunoblotting, qPCR and mRNA fluorescent in-situ hybridization (mRNA-FISH) were conducted on LV tissue and cells. RESULTS: ECM1 expression was upregulated in the aging LV, and in the infarct zone of the LV early post-MI. No significant differences in ECM1 expression were found late post-MI or at any time-point post-TAC. ECM1 was not expressed in any resident cardiac cells, but ECM1 was highly expressed in BMCs, with high ECM1 expression in granulocytes. Flow cytometry of bone marrow revealed ECM1 expression in large granular leucocytes. mRNA-FISH revealed that ECM1 was indeed expressed by inflammatory cells in the infarct zone at day-3 post-MI. ECM1 stimulation of CFbs induced ERK1/2 and AKT activation and collagen-I expression, suggesting a pro-fibrotic role. CONCLUSIONS: ECM1 expression is increased in ageing and infarcted hearts but is not expressed by resident cardiac cells. Instead it is expressed by bone marrow-derived granulocytes. ECM1 is sufficient to induce cardiac fibroblast stimulation in vitro. Our findings suggest ECM1 is released from infiltrating inflammatory cells, which leads to cardiac fibroblast stimulation and fibrosis in aging and MI. ECM1 may be a novel intermediary between inflammation and fibrosis. FAU - Hardy, Sean A AU - Hardy SA AD - School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia. AD - Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. FAU - Mabotuwana, Nishani S AU - Mabotuwana NS AD - School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia. AD - Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. FAU - Murtha, Lucy A AU - Murtha LA AD - School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia. AD - Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. FAU - Coulter, Brianna AU - Coulter B AD - School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia. AD - Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. FAU - Sanchez-Bezanilla, Sonia AU - Sanchez-Bezanilla S AUID- ORCID: 0000-0003-2753-2691 AD - School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia. AD - Priority Research Centre's for Healthy Lungs and GrowUpWell, School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia. FAU - Al-Omary, Mohammed S AU - Al-Omary MS AD - School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia. AD - Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. AD - Department of Cardiovascular Medicine, John Hunter Hospital, New Lambton Heights, NSW, Australia. FAU - Senanayake, Tharindu AU - Senanayake T AD - School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia. FAU - Loering, Svenja AU - Loering S AD - Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. AD - School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia. AD - Priority Research Centre's for Healthy Lungs and GrowUpWell, School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia. FAU - Starkey, Malcolm AU - Starkey M AD - Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. AD - School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia. AD - Priority Research Centre's for Healthy Lungs and GrowUpWell, School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia. FAU - Lee, Randall J AU - Lee RJ AD - Department of Medicine, Division of Cardiology, University of California San Francisco, San Francisco, CA, United States of America. AD - Edyth and Eli Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, United States of America. FAU - Rainer, Peter P AU - Rainer PP AD - Division of Cardiology, Medical University of Graz, Graz, Austria. FAU - Hansbro, Philip M AU - Hansbro PM AD - Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. AD - School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia. AD - Priority Research Centre's for Healthy Lungs and GrowUpWell, School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia. AD - Centre for inflammation, Centenary Institute, Sydney, NSW, Australia. AD - University of Technology, Faculty of Science, Ultimo, NSW, Australia. FAU - Boyle, Andrew J AU - Boyle AJ AD - School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia. AD - Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. AD - Department of Cardiovascular Medicine, John Hunter Hospital, New Lambton Heights, NSW, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190221 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (ECM1 protein, human) RN - 0 (Ecm1 protein, mouse) RN - 0 (Extracellular Matrix Proteins) SB - IM MH - Aging/*metabolism/pathology MH - Animals MH - Extracellular Matrix Proteins/*biosynthesis MH - Female MH - *Gene Expression Regulation MH - Heart Ventricles/metabolism/pathology MH - Humans MH - Male MH - Mice MH - Myocardial Infarction/*metabolism/pathology MH - Myocardium/*metabolism/pathology PMC - PMC6383988 COIS- The authors have declared that no competing interests exist. EDAT- 2019/02/23 06:00 MHDA- 2019/11/14 06:00 PMCR- 2019/02/21 CRDT- 2019/02/22 06:00 PHST- 2018/11/05 00:00 [received] PHST- 2019/01/29 00:00 [accepted] PHST- 2019/02/22 06:00 [entrez] PHST- 2019/02/23 06:00 [pubmed] PHST- 2019/11/14 06:00 [medline] PHST- 2019/02/21 00:00 [pmc-release] AID - PONE-D-18-31882 [pii] AID - 10.1371/journal.pone.0212230 [doi] PST - epublish SO - PLoS One. 2019 Feb 21;14(2):e0212230. doi: 10.1371/journal.pone.0212230. eCollection 2019.