Author:
Murtha Lucy A.,Hardy Sean A.,Mabotuwana Nishani S.,Bigland Mark J.,Bailey Taleah,Raguram Kalyan,Liu Saifei,Ngo Doan T.,Sverdlov Aaron L.,Tomin Tamara,Birner-Gruenberger Ruth,Hume Robert D.,Iismaa Siiri E.,Humphreys David T.,Patrick Ralph,Chong James J. H.,Lee Randall J.,Harvey Richard P.,Graham Robert M.,Rainer Peter P.,Boyle Andrew J.
Abstract
AbstractDespite 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 organisation 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.
Funder
John Hunter Charitable Trust
Hunter Medical Research Institute
RT Hall Trust
Austrian Science Foundation and ERA-CVD project AIR-MI funding
Austrian Science Fund
Austrian Ministry of Science Research and Economy
Austrian Herzfonds
National Heart Foundation of Australia
New South Wales Health and Sydney Medical School Foundation
National Health and Medical Research Council
Victor Chang Cardiac Research Institute
Publisher
Springer Science and Business Media LLC