WNT/β-Catenin Signaling Promotes TGF-β-Mediated Activation of Human Cardiac Fibroblasts by Enhancing IL-11 Production

Cardiac fibrosis is a pathological process associated with the development of heart failure. TGF-beta 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-beta-activated human cardiac fibroblasts. We found that WNT3a and TGF-beta induced a beta-catenin-dependent response, whereas WNT5a prompted AP-1 activity. TGF-beta triggered profibrotic signatures in cardiac fibroblasts, and co-stimulation with WNT3a or co-activation of the beta-catenin pathway with the GSK3 beta inhibitor CHIR99021 enhanced collagen I and fibronectin production and development of active contractile stress fibers. In the absence of TGF-beta, neither WNT3a nor CHIR99021 exerted profibrotic responses. On a molecular level, in TGF-beta-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-beta and WNT3a. In contrast to canonical WNT3a, co-activation with non-canonical WNT5a suppressed TGF-beta-induced production of collagen I. In conclusion, WNT/beta-catenin signaling promotes TGF-beta-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.

Automated summary

The study revealed that WNT/beta-catenin signaling promotes the transition of cardiac fibroblasts to myofibroblasts by enhancing IL-11 production in TGF-beta-mediated pathways, while non-canonical WNT5a co-activation suppressed TGF-beta-induced collagen I production.