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SHR Neuro Cancer Cardio Lipid Metab Microb

Blyszczuk, P; Müller-Edenborn, B; Valenta, T; Osto, E; Stellato, M; Behnke, S; Glatz, K; Basler, K; Lüscher, TF; Distler, O; Eriksson, U; Kania, G.
Transforming growth factor-β-dependent Wnt secretion controls myofibroblast formation and myocardial fibrosis progression in experimental autoimmune myocarditis.
Eur Heart J. 2017; 38(18):1413-1425 Doi: 10.1093/eurheartj/ehw116
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Co-authors Med Uni Graz

Osto Elena

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Abstract:

AIMS: Myocardial fibrosis critically contributes to cardiac dysfunction in inflammatory dilated cardiomyopathy (iDCM). Activation of transforming growth factor-β (TGF-β) signalling is a key-step in promoting tissue remodelling and fibrosis in iDCM. Downstream mechanisms controlling these processes, remain elusive. METHODS AND RESULTS: Experimental autoimmune myocarditis (EAM) was induced in BALB/c mice with heart-specific antigen and adjuvant. Using heart-inflammatory precursors, as well as mouse and human cardiac fibroblasts, we demonstrated rapid secretion of Wnt proteins and activation of Wnt/β-catenin pathway in response to TGF-β signalling. Inactivation of extracellular Wnt with secreted Frizzled-related protein 2 (sFRP2) or inhibition of Wnt secretion with Wnt-C59 prevented TGF-β-mediated transformation of inflammatory precursors and cardiac fibroblasts into pathogenic myofibroblasts. Inhibition of T-cell factor (TCF)/β-catenin-mediated transcription with ICG-001 or genetic loss of β-catenin also prevented TGF-β-induced myofibroblasts formation. Furthermore, blocking of Smad-independent TGF-β-activated kinase 1 (TAK1) pathway completely abrogated TGF-β-induced Wnt secretion. Activation of Wnt pathway in the absence of TGF-β, however, failed to transform precursors into myofibroblasts. The critical role of Wnt axis for cardiac fibrosis in iDCM is also supported by elevated Wnt-1/Wnt-5a levels in human samples from hearts with myocarditis. Accordingly, and as an in vivo proof of principle, inhibition of Wnt secretion or TCF/β-catenin-mediated transcription abrogated the development of post-inflammatory fibrosis in EAM. CONCLUSION: We identified TAK1-mediated rapid Wnt protein secretion as a novel downstream key mechanism of TGF-β-mediated myofibroblast differentiation and myocardial fibrosis progression in human and mouse myocarditis. Thus, pharmacological targeting of Wnts might represent a promising therapeutic approach against iDCM in the future.

Find related publications in this database (using NLM MeSH Indexing)

Animals - administration & dosage

Autoimmune Diseases - etiology

Benzeneacetamides - pharmacology

Cell Differentiation - physiology

Disease Progression - administration & dosage

Fibrosis - physiopathology

Humans - administration & dosage

MAP Kinase Kinase Kinases - metabolism, physiology

Membrane Proteins - metabolism

Mice, Inbred BALB C - administration & dosage

Myocarditis - etiology

Myocardium - pathology

Myofibroblasts - physiology

Pyridines - pharmacology

Signal Transduction - physiology

Stem Cells - physiology

TCF Transcription Factors - metabolism

Transforming Growth Factor beta - physiology

Ventricular Dysfunction - physiopathology

Wnt Proteins - metabolism

Wnt-5a Protein - metabolism

Wnt1 Protein - metabolism

beta Catenin - metabolism

Find related publications in this database (Keywords)

Experimental autoimmune myocarditis

CD133 inflammatory progenitor

Cardiac fibroblasts

Myofibroblast

TGF-beta signalling

Wnt-TAK1 signalling

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