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

Murtha, Lucy A. and Hardy, Sean A. and Mabotuwana, Nishani S. and Bigland, Mark J. and Bailey, Taleah and Raguram, Kalyan and Liu, Saifei and Ngo, Doan T. and Sverdlov, Aaron L. and Tomin, Tamara and Birner-Gruenberger, Ruth and Hume, Robert D. and Iismaa, Siiri E. and Humphreys, David T. and Patrick, Ralph and Chong, James J. H. and Lee, Randall J. and Harvey, Richard P. and Graham, Robert M. and Rainer, Peter P. and Boyle, Andrew J. (2023) Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction. Scientific Reports, 13 (1). ISSN 2045-2322

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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 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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 01 May 2024 04:52
Last Modified: 01 May 2024 04:52

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