WNT/β-Catenin Signaling Promotes TGF-β-Mediated Activation of Human Cardiac Fibroblasts by Enhancing IL-11 Production
| Autor: | Gabriela Kania, Maciej Siedlar, Przemyslaw Blyszczuk, Karolina Tkacz, Marcin Czepiel, Edyta Działo |
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| Přispěvatelé: | University of Zurich, Błyszczuk, Przemysław |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cardiac fibrosis
cardiac fibrosis 1607 Spectroscopy SMAD TGF-β signaling Pathogenesis Stress Fibers RNA-Seq Biology (General) WNT5a Myofibroblasts Wnt Signaling Pathway Spectroscopy cardiac fibroblasts beta Catenin biology Chemistry Wnt signaling pathway 10051 Rheumatology Clinic and Institute of Physical Medicine Heart General Medicine Interleukin-11 MAP Kinase Kinase Kinases Computer Science Applications Cell biology embryonic structures IL-11 Phosphorylation Collagen 1606 Physical and Theoretical Chemistry Signal Transduction QH301-705.5 1503 Catalysis 610 Medicine & health Catalysis Article Wnt-5a Protein Inorganic Chemistry Transforming Growth Factor beta1 Wnt3A Protein medicine 1312 Molecular Biology 1706 Computer Science Applications Humans Physical and Theoretical Chemistry Molecular Biology QD1-999 WNT3a 1604 Inorganic Chemistry Myocardium Organic Chemistry β-catenin Fibroblasts medicine.disease Fibrosis Fibronectin body regions Wnt Proteins biology.protein WNT3A Transforming growth factor 1605 Organic Chemistry |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 18 International Journal of Molecular Sciences, Vol 22, Iss 10072, p 10072 (2021) |
| ISSN: | 1422-0067 |
| Popis: | Cardiac fibrosis is a pathological process associated with the development of heart failure. TGF-β and WNT signaling have been implicated in pathogenesis of cardiac fibrosis, however, little is known about molecular cross-talk between these two pathways. The aim of this study was to examine the effect of exogenous canonical WNT3a and non-canonical WNT5a in TGF-β-activated human cardiac fibroblasts. We found that WNT3a and TGF-β induced a β-catenin-dependent response, whereas WNT5a prompted AP-1 activity. TGF-β triggered profibrotic signatures in cardiac fibroblasts, and co-stimulation with WNT3a or co-activation of the β-catenin pathway with the GSK3β inhibitor CHIR99021 enhanced collagen I and fibronectin production and development of active contractile stress fibers. In the absence of TGF-β, neither WNT3a nor CHIR99021 exerted profibrotic responses. On a molecular level, in TGF-β-activated fibroblasts, WNT3a enhanced phosphorylation of TAK1 and production and secretion of IL-11 but showed no effect on the Smad pathway. Neutralization of IL-11 activity with the blocking anti-IL-11 antibody effectively reduced the profibrotic response of cardiac fibroblasts activated with TGF-β and WNT3a. In contrast to canonical WNT3a, co-activation with non-canonical WNT5a suppressed TGF-β-induced production of collagen I. In conclusion, WNT/β-catenin signaling promotes TGF-β-mediated fibroblast-to-myofibroblast transition by enhancing IL-11 production. Thus, the uncovered mechanism broadens our knowledge on a molecular basis of cardiac fibrogenesis and defines novel therapeutic targets for fibrotic heart diseases. |
| Databáze: | OpenAIRE |
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