Przemyslaw Blyszczuk1,2,3, Björn Müller-Edenborn1,3, Tomas Valenta4, Elena Osto5,6, Mara Stellato7, Silvia Behnke8, Katharina Glatz9, Konrad Basler4, Thomas F Lüscher5,10, Oliver Distler7, Urs Eriksson1,3, Gabriela Kania7. 1. Cardioimmunology, Center for Molecular Cardiology, University of Zurich, Wagistr. 12, CH-8952 Schlieren, Switzerland. 2. Department of Clinical Immunology, Jagiellonian University Medical College, Wielicka 265, 30-663 Cracow, Poland. 3. Department of Medicine, GZO-Zurich Regional Health Center, Spitalstr. 66, CH-8620 Wetzikon, Switzerland. 4. Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland. 5. Center for Molecular Cardiology, University of Zurich, Wagistr. 12, CH-8952 Schlieren, Switzerland. 6. ETH Zurich, Institute of Food, Nutrition and Health, Laboratory of Translational Nutrition Biology, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland. 7. Research of Systemic Autoimmune Diseases, Division of Rheumatology, University Hospital Zurich, Wagistr. 14, CH-8952 Schlieren, Switzerland. 8. Sophistolab AG, Hofackerstrasse 40A, 4132 Muttenz, Switzerland. 9. Institute of Pathology, University Hospital, Hebelstr. 20, CH-4031 Basle, Switzerland. 10. Department of Cardiology, University Heart Center, University Hospital Zurich, Raemistr. 100, CH-8001 Zurich, Switzerland.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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