Abstract
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.
Highlights
Cardiac fibrosis refers to the excessive accumulation of stromal cells and extracellular matrix (ECM) components in the myocardium and is often associated with cardiac pathologies
Our results indicate that WNT/β-catenin controls profibrotic interleukin 11 (IL-11) in TGF-β-dependent fibroblast-to-myofibroblast transitions
Before investigating the effect of WNT signaling on the differentiation of human cardiac fibroblasts, we addressed their responsiveness to exogenous WNT3a and WNT5a
Summary
Cardiac fibrosis refers to the excessive accumulation of stromal cells and extracellular matrix (ECM) components in the myocardium and is often associated with cardiac pathologies. Fibrotic scar develops following myocardial infarction to support tissue integrity and regeneration. Hypertension, cardiomyopathy, local and systemic inflammation, co-morbidities, certain medications and aging may cause pathological tissue remodeling, affecting cardiac function [1]. Increased stiffness of cardiac tissue and disturbed propagation of electrical impulses are direct outcomes of fibrosis, and these changes may lead to heart failure and arrhythmias [2]. Patients with persistent cardiac fibrosis show longer hospitalization and increased mortality [3]. Late gadolinium-enhancement cardiac magnetic resonance identified fibrotic scars in up to one fourth of infarcted hearts [4], and in 31–38% of non-ischemic cardiomyopathy patients [5,6]. Post-mortem histopathology studies reported fibrosis in every fifth heart of sudden cardiac death [7] and COVID-19 victims [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
