Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction

Author:

Murtha Lucy A.1,Hardy Sean A.1,Mabotuwana Nishani S.1,Bigland Mark J.1,Bailey Taleah1,Raguram Kalyan1,Liu Saifei2,Ngo Doan T.1,Sverdlov Aaron L.1,Tomin Tamara3,Birner-Gruenberger Ruth3,Hume Robert D.4,Iismaa Siiri E.5,Humphreys David T.5,Patrick Ralph5,Chong James J.H.4,Lee Randall J.6,Harvey Richard P.5,Graham Robert M.5,Rainer Peter P.7,Boyle Andrew J.1

Affiliation:

1. Faculty of Health and Medicine, The University of Newcastle

2. Department of Cardiology and Clinical Pharmacology, Basil Hetzel Institute, The University of Adelaide, The Queen Elizabeth Hospital

3. Institute of Chemical Technologies and Analytics, Faculty of Technical Chemistry, Technische Universität Wien

4. Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney

5. Victor Chang Cardiac Research Institute

6. Department of Medicine, Division of Cardiology, University of California San Francisco

7. Division of Cardiology, Medical University of Graz

Abstract

Abstract Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1-/-) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3-6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in Fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organization pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.

Publisher

Research Square Platform LLC

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