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Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction.
- Murtha, Lucy;
- Hardy, Sean;
- Mabotuwana, Nishani;
- Bigland, Mark;
- Bailey, Taleah;
- Raguram, Kalyan;
- Liu, Saifei;
- Ngo, Doan;
- Sverdlov, Aaron;
- Tomin, Tamara;
- Birner-Gruenberger, Ruth;
- Hume, Robert;
- Iismaa, Siiri;
- Humphreys, David;
- Patrick, Ralph;
- Chong, James;
- Harvey, Richard;
- Graham, Robert;
- Rainer, Peter;
- Boyle, Andrew;
- Lee, Randall
- et al.
Published Web Location
https://doi.org/10.1038/s41598-023-41894-9Abstract
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.
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