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Transforming growth factor-β-dependent Wnt secretion controls myofibroblast formation and myocardial fibrosis progression in experimental autoimmune myocarditis


Blyszczuk, Przemyslaw; Müller-Edenborn, Björn; Valenta, Tomas; Osto, Elena; Stellato, Mara; Behnke, Silvia; Glatz, Katharina; Basler, Konrad; Lüscher, Thomas F; Distler, Oliver; Eriksson, Urs; Kania, Gabriela (2017). Transforming growth factor-β-dependent Wnt secretion controls myofibroblast formation and myocardial fibrosis progression in experimental autoimmune myocarditis. European Heart Journal, 38(18):1413-1425.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
07 Faculty of Science > Institute of Molecular Life Sciences
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:7 May 2017
Deposited On:29 Apr 2016 17:54
Last Modified:09 May 2017 01:00
Publisher:Oxford University Press
ISSN:0195-668X
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/eurheartj/ehw116
PubMed ID:27099262

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