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Reese-Petersen, A L; Karsdal, M; Genovese, F
European heart journal, 10/2019, Letnik: 40, Številka: Supplement_1Journal Article
Abstract Background/Aim Accumulation of extracellular matrix (ECM) proteins is the hallmark of cardiac fibrosis, causing stiffening of the ventricular wall, which can lead to heart failure and ultimately death. Many different cell types and growth factors are involved in this process but fibroblasts are the main source of ECM proteins. Here we present results from an in vitro model indicating that endotrophin (ETP), a collagen type VI fragment, activates cardiac fibroblasts and induces fibrogenesis. Methods The effect of ETP, transforming growth factor (TGF)-β and platelet-derived growth factor (PDGF)-DD on ECM protein synthesis was assessed in a scar-in-a-jar (SiaJ) cell model using human cardiac fibroblasts isolated from the atrium of an adult healthy donor. Cells were seeded in 48-well plates at a density of 30.000 cells/well and incubated for 24H in Dulbecco's Modified Eagle's medium (DMEM) + 10% fetal bovine serum (FBS). Serum starvation was done by seeding the cells for further 24H in DMEM + 0.4% FBS. Fresh medium was added at day 0 with 37.5/25mg/mL Ficoll 70/400 and 1% ascorbic acid, containing 11.75 nM human recombinant ETP, 0.04 nM TGF-β, 0.39 nM PDGF-DD or a vehicle control. Medium was changed and collected at day 3 and 6. Biomarkers of type I (PRO-C1), III (PRO-C3), VI (PRO-C6) collagens and fibronectin (FBN-C) formation were assessed in the medium by ELISAs developed at Nordic Bioscience. Results ETP induced a significant increase in PRO-C1, PRO-C3 and FBN-C (comparable to TGF-β and PDGF-DD) within the first three days of the experiment, compared to the vehicle control. The levels remained significantly increased for PRO-C3 and FBN-C throughout the experiment, and non-significantly elevated for PRO-C1, compared to the vehicle control. PDGF-DD significantly induced synthesis of type VI collagen compared to the vehicle control, while TGF-β induced a small increase in synthesis from day 0–3, after which it seemed to inhibit synthesis. Conclusion For the first time, a direct pro-fibrotic effect on fibroblasts induced by ETP has been shown. This novel pathway of activation could play an important role in regulating cardiac fibrosis, and thus prove to be a therapeutic target. This SiaJ model in combination with the investigated biomarkers of ECM formation could be used to further elucidate the mechanisms behind cardiac fibrosis.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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