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- Title
Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction.
- Authors
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.
- 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 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.
- Subjects
MYOCARDIAL infarction; EXTRACELLULAR matrix proteins; KNOCKOUT mice; GENE knockout; HEART failure patients
- Publication
Scientific Reports, 2023, Vol 13, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-023-41894-9