Autor: |
Lucy A. Murtha, Sean A. Hardy, Nishani S. Mabotuwana, Mark J. Bigland, Taleah Bailey, Kalyan Raguram, Saifei Liu, Doan T. Ngo, Aaron L. Sverdlov, Tamara Tomin, Ruth Birner-Gruenberger, Robert D. Hume, Siiri E. Iismaa, David T. Humphreys, Ralph Patrick, James J. H. Chong, Randall J. Lee, Richard P. Harvey, Robert M. Graham, Peter P. Rainer, Andrew J. Boyle |
Jazyk: |
angličtina |
Rok vydání: |
2023 |
Předmět: |
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Zdroj: |
Scientific Reports, Vol 13, Iss 1, Pp 1-12 (2023) |
Druh dokumentu: |
article |
ISSN: |
2045-2322 |
DOI: |
10.1038/s41598-023-41894-9 |
Popis: |
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. |
Databáze: |
Directory of Open Access Journals |
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