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

被引：185

作者：

Blyszczuk, Przemyslaw ^{[1
,2
,3
]}

Mueller-Edenborn, Bjorn ^{[1
,3
]}

Valenta, Tomas ^{[4
]}

Osto, Elena ^{[5
,6
]}

Stellato, Mara ^{[7
]}

Behnke, Silvia ^{[8
]}

Glatz, Katharina ^{[9
]}

Basler, Konrad ^{[4
]}

Luscher, Thomas F. ^{[5
,10
]}

Distler, Oliver ^{[7
]}

Eriksson, Urs ^{[1
,3
]}

Kania, Gabriela ^{[7
]}

机构：

[1] Univ Zurich, Ctr Mol Cardiol, Cardioimmunol, Wagistr 12, CH-8952 Schlieren, Switzerland

[2] Jagiellonian Univ, Coll Med, Dept Clin Immunol, Wielicka 265, PL-30663 Krakow, Poland

[3] GZO Zurich Reg Hlth Ctr, Dept Med, Spitalstr 66, CH-8620 Wetzikon, Switzerland

[4] Univ Zurich, Inst Mol Life Sci, Winterthurerstr 190, CH-8057 Zurich, Switzerland

[5] Univ Zurich, Ctr Mol Cardiol, Wagistr 12, CH-8952 Schlieren, Switzerland

[6] Swiss Fed Inst Technol, Inst Food Nutr & Hlth, Lab Translat Nutr Biol, Schorenstr 16, CH-8603 Schwerzenbach, Switzerland

[7] Univ Zurich Hosp, Div Rheumatol, Res Syst Autoimmune Dis, Wagistr 14, CH-8952 Schlieren, Switzerland

[8] Sophistolab AG, Hofackerstr 40A, CH-4132 Muttenz, Switzerland

[9] Univ Hosp, Inst Pathol, Hebelstr 20, CH-4031 Basel, Switzerland

[10] Univ Zurich Hosp, Univ Heart Ctr, Dept Cardiol, Raemistr 100, CH-8001 Zurich, Switzerland

来源：

EUROPEAN HEART JOURNAL | 2017年 / 38卷 / 18期

关键词：

Experimental autoimmune myocarditis; CD133 inflammatory progenitor; Cardiac fibroblasts; Myofibroblast; TGF-beta signalling; Wnt-TAK1; signalling; CATENIN; INFARCTION; HEART; INHIBITION; CELLS; APC;

D O I：

10.1093/eurheartj/ehw116

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims Myocardial fibrosis critically contributes to cardiac dysfunction in inflammatory dilated cardiomyopathy (iDCM). Activation of transforming growth factor-beta (TGF-beta) 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/b-catenin pathway in response to TGF-beta signalling. Inactivation of extracellular Wnt with secreted Frizzled-related protein 2 (sFRP2) or inhibition of Wnt secretion with Wnt-C59 prevented TGF-beta-mediated transformation of inflammatory precursors and cardiac fibroblasts into pathogenic myofibroblasts. Inhibition of T-cell factor (TCF)/beta-catenin-mediated transcription with ICG-001 or genetic loss of beta-catenin also prevented TGF-beta-induced myofibroblasts formation. Furthermore, blocking of Smad-independent TGF-beta-activated kinase 1 (TAK1) pathway completely abrogated TGF-beta-induced Wnt secretion. Activation of Wnt pathway in the absence of TGF-beta, 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/beta-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-beta-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.

引用

页码：1413 / 1425

页数：13

共 29 条

[1] Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis [J].